SPINK5 (serine peptidase inhibitor Kazal type 5)

Gene

• Entrez ID: 11005
• Gene name: Serine peptidase inhibitor Kazal type 5
• Gene symbol: SPINK5
• Synonyms (NCBI Gene): LEKTI, LETKI, NETS, NS, VAKTI
• Chromosome: 5
• Chromosome location: 5q32
• Summary: This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. T

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121908387	C>T	Pathogenic	Stop gained, coding sequence variant
rs142227576	G>A,T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant
rs142558269	C>G,T	Conflicting-interpretations-of-pathogenicity, benign-likely-benign	Coding sequence variant, missense variant
rs181639116	A>G	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant
rs199757347	C>G,T	Pathogenic	Missense variant, coding sequence variant, stop gained
rs201269335	A>T	Pathogenic	Intron variant
rs367958902	C>T	Pathogenic	Coding sequence variant, stop gained
rs368134354	G>A,C,T	Pathogenic, likely-pathogenic	Intron variant
rs373463881	C>G,T	Pathogenic	Missense variant, coding sequence variant, stop gained
rs565782662	AAA>-,A,AA,AAAA,AAAAAAA	Pathogenic	Coding sequence variant, frameshift variant, inframe deletion
rs587777749	A>T	Pathogenic	Splice acceptor variant
rs748978134	->A	Pathogenic	Coding sequence variant, frameshift variant
rs752777832	T>C,G	Pathogenic	Stop gained, coding sequence variant, synonymous variant
rs752941297	C>T	Pathogenic, likely-pathogenic	Coding sequence variant, synonymous variant
rs753621591	C>T	Pathogenic	Stop gained, coding sequence variant
rs756874525	->GTGC	Pathogenic	Frameshift variant, coding sequence variant
rs759255682	G>A	Pathogenic	Splice acceptor variant
rs761490126	AA>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs766028970	C>T	Pathogenic	Coding sequence variant, stop gained
rs766978225	T>A	Conflicting-interpretations-of-pathogenicity	Genic downstream transcript variant, coding sequence variant, stop gained
rs769519367	T>-	Conflicting-interpretations-of-pathogenicity	Stop lost, intron variant, terminator codon variant, frameshift variant
rs775341740	G>A	Pathogenic	Splice donor variant
rs886039547	C>T	Pathogenic	Coding sequence variant, stop gained
rs886041508	A>T	Pathogenic	Coding sequence variant, stop gained
rs1057518067	G>C	Likely-pathogenic	Genic downstream transcript variant, splice acceptor variant
rs1057518161	T>C	Pathogenic	Splice donor variant
rs1057520643	T>A,C	Pathogenic	Stop gained, synonymous variant, coding sequence variant
rs1057524476	G>A	Pathogenic	Splice acceptor variant
rs1131691490	T>A	Pathogenic	Splice donor variant, 5 prime UTR variant
rs1131691815	G>-	Pathogenic	Coding sequence variant, frameshift variant
rs1362009010	A>-	Pathogenic	Frameshift variant, coding sequence variant
rs1419297868	C>-	Pathogenic	Coding sequence variant, frameshift variant
rs1554104853	A>-	Pathogenic	Coding sequence variant, frameshift variant
rs1554105045	C>A	Pathogenic	Coding sequence variant, stop gained
rs1554105205	GAAGA>-	Pathogenic	Coding sequence variant, frameshift variant
rs1561680487	TTGT>-	Pathogenic	Frameshift variant, coding sequence variant
rs1561684604	A>-	Pathogenic	Frameshift variant, coding sequence variant
rs1561686960	T>-	Pathogenic	Frameshift variant, coding sequence variant
rs1561695740	TTCTTGTGAGTGGGCGGCAGCCACTG>CT	Pathogenic	Intron variant, splice donor variant, coding sequence variant
rs1561701382	G>A	Likely-pathogenic	Splice donor variant
rs1581064755	TGTGGCACAGATGGGAA>GACAACATATGACAACAGATGAC	Pathogenic	Coding sequence variant, stop gained, inframe indel
rs1581074967	G>-	Pathogenic	Coding sequence variant, frameshift variant
rs1581096271	TT>-	Pathogenic	Coding sequence variant, frameshift variant
rs1581109809	A>-	Pathogenic	Frameshift variant, coding sequence variant, genic downstream transcript variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT018086	hsa-miR-335-5p	Microarray	18185580
MIRT755526	hsa-miR-5100	Luciferase reporter assay, Western blotting, qRT-PCR, Immunoprecipitaion (IP), Immunohistochemistry (IHC), in vitro cullelar assays, Immunofluorescence	35705923
MIRT1384454	hsa-miR-3174	CLIP-seq
MIRT1384455	hsa-miR-4276	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0002787	Process	Negative regulation of antibacterial peptide production	IEA
GO:0004867	Function	Serine-type endopeptidase inhibitor activity	IBA
GO:0004867	Function	Serine-type endopeptidase inhibitor activity	IDA	10419450, 15680911
GO:0004867	Function	Serine-type endopeptidase inhibitor activity	IEA
GO:0005576	Component	Extracellular region	IBA
GO:0005576	Component	Extracellular region	IDA	15680911
GO:0005576	Component	Extracellular region	IEA
GO:0005576	Component	Extracellular region	NAS	10419450
GO:0005576	Component	Extracellular region	TAS
GO:0005737	Component	Cytoplasm	IDA	12915442
GO:0005783	Component	Endoplasmic reticulum	IDA	15680911
GO:0005789	Component	Endoplasmic reticulum membrane	IDA	15680911
GO:0005829	Component	Cytosol	IDA	15680911
GO:0005938	Component	Cell cortex	IDA	12915442
GO:0009913	Process	Epidermal cell differentiation	IDA	12915442
GO:0016525	Process	Negative regulation of angiogenesis	TAS	15680911
GO:0030154	Process	Cell differentiation	IBA
GO:0030155	Process	Regulation of cell adhesion	IEA
GO:0030198	Process	Extracellular matrix organization	TAS	15680911
GO:0030414	Function	Peptidase inhibitor activity	IEA
GO:0030855	Process	Epithelial cell differentiation	TAS	12915442
GO:0035315	Process	Hair cell differentiation	TAS	12915442
GO:0045580	Process	Regulation of T cell differentiation	TAS	12915442
GO:0045861	Process	Negative regulation of proteolysis	IEA
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	15680911
GO:0050777	Process	Negative regulation of immune response	TAS	12915442
GO:0051884	Process	Regulation of timing of anagen	TAS	12915442
GO:0097209	Component	Epidermal lamellar body	IDA	15675955

Other IDs

• MIM: 605010
• HGNC: 15464
• e!Ensembl: ENSG00000133710

Protein

• UniProt ID: Q9NQ38
• Protein name: Serine protease inhibitor Kazal-type 5 (Lympho-epithelial Kazal-type-related inhibitor) (LEKTI) [Cleaved into: Hemofiltrate peptide HF6478; Hemofiltrate peptide HF7665]
• Protein function: Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating
• PDB: 1H0Z, 1HDL, 1UUC, 1UVF, 1UVG, 5YHN
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF07648	Kazal_2	106 → 151	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	161 → 211	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	225 → 273	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	297 → 348	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	437 → 487	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	496 → 548	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	631 → 684	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	707 → 758	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	774 → 826	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	916 → 962	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	993 → 1046	Kazal-type serine protease inhibitor domain	Domain

• Tissue specificity: TISSUE SPECIFICITY: Highly expressed in the thymus and stratum corneum. Also found in the oral mucosa, parathyroid gland, Bartholin's glands, tonsils, and vaginal epithelium. Very low levels are detected in lung, kidney, and prostate. {ECO:0000269|PubMed:
• Sequence:

  MKIATVSVLLPLALCLIQDAASKNEDQEMCHEFQAFMKNGKLFCPQDKKFFQSLDGIMFI
  NKCATCKMILEKEAKSQKRARHLARAPKATAPTELNCDDFKKGERDGDFICPDYYEAVCG
  TDGKTYDNRCALCAENAKTGSQIGVKSEGECKSSNPEQDVCSAFRPFVRDGRLGCTREND
  PVLGPDGKTHGNKCAMCAELFLKEAENAKREGETRIRRNAEKDFCKEYEKQVRNGRLFCT
  RESDPVRGPDGRMHGNKCALCAEIFKQRFSEENSKTDQNLGKAEEKTKVKREIVKLCSQY
  QNQAKNGILFCTRENDPIRGPDGKMHGNLCSMCQAYFQAENEEKKKAEARARNKRESGKA
  TSYAELCSEYRKLVRNGKLACTRENDPIQGPDGKVHGNTCSMCEVFFQAEEEEKKKKEGK
  SRNKRQSKSTASFEELCSEYRKSRKNGRLFCTRENDPIQGPDGKMHGNTCSMCEAFFQQE
  ERARAKAKREAAKEICSEFRDQVRNGTLICTREHNPVRGPDGKMHGNKCAMCASVFKLEE
  EEKKNDKEEKGKVEAEKVKREAVQELCSEYRHYVRNGRLPCTRENDPIEGLDGKIHGNTC
  SMCEAFFQQEAKEKERAEPRAKVKREAEKETCDEFRRLLQNGKLFCTRENDPVRGPDGKT
  HGNKCAMCKAVFQKENEERKRKEEEDQRNAAGHGSSGGGGGNTQDECAEYREQMKNGRLS
  CTRESDPVRDADGKSYNNQCTMCKAKLEREAERKNEYSRSRSNGTGSESGKDTCDEFRSQ
  MKNGKLICTRESDPVRGPDGKTHGNKCTMCKEKLEREAAEKKKKEDEDRSNTGERSNTGE
  RSNDKEDLCREFRSMQRNGKLICTRENNPVRGPYGKMHINKCAMCQSIFDREANERKKKD
  EEKSSSKPSNNAKDECSEFRNYIRNNELICPRENDPVHGADGKFYTNKCYMCRAVFLTEA
  LERAKLQEKPSHVRASQEEDSPDSFSSLDSEMCKDYRVLPRIGYLCPKDLKPVCGDDGQT
  YNNPCMLCHENLIRQTNTHIRSTGKCEESSTPGTTAASMPPSDE

• Sequence length: 1064

Pathways

Reactome:

Formation of the cornified envelope

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Erythroderma	Likely pathogenic; Pathogenic	rs368134354, rs752941297	RCV000414954 RCV000415446	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Ichthyosis linearis circumflexa	Pathogenic; Likely pathogenic	rs2113177526, rs1309309448, rs192473445, rs1754451124, rs773865874, rs1480221716, rs2113120213, rs2113195147, rs2113120242, rs750789505, rs1754362343, rs776293648, rs2531649877, rs567566682, rs121908387, rs565782662, rs1754222214, rs2531788776, rs2531706238, rs2531776765, rs770450773, rs765752936, rs201269335, rs748978134, rs773514258, rs761010013, rs2531807956, rs2531776726, rs767816225, rs776976720, rs2531782406, rs2531711888, rs2531690264, rs2531787857, rs1219497521, rs1754033945, rs766754092, rs1754569068, rs769549131, rs766316221, rs1057518067, rs368134354, rs775341740, rs752941297, rs1057520643, rs756874525, rs1131691490, rs373463881, rs766978225, rs367958902, rs1554105045, rs1554104853, rs1561701382, rs1561684604, rs753621591, rs1581064755, rs1419297868, rs1581074967, rs752777832, rs1581096271, rs1362009010, rs759255682, rs1394583450, rs1366194827, rs1212676320, rs749828824, rs771730802, rs763649250, rs1221030255, rs924297783, rs1340491788, rs1482249008, rs777436361	RCV003761217 RCV003761403 RCV003762054 RCV003772929 RCV003773286 RCV003762055 RCV003772935 RCV003762011 RCV003772957 RCV003597237 RCV003762117 RCV003597226 RCV003596182 RCV003596216 RCV003595852 RCV003492286 RCV005059032 RCV003763249 RCV003764021 RCV003764010 RCV003596124 RCV003764137 RCV003595905 RCV003595906 RCV005103915 RCV003596332 RCV003596411 RCV003596850 RCV003596851 RCV003762289 RCV003762284 RCV003762282 RCV003762418 RCV003762691 RCV003763290 RCV003763524 RCV003763554 RCV003764343 RCV003823546 RCV003847298 RCV003761967 RCV003595955 RCV003595956 RCV003595957 RCV003761982 RCV003595991 RCV003596007 RCV003596010 RCV003596033 RCV003596076 RCV005056353 RCV003762844 RCV003596083 RCV003596517 RCV003596505 RCV003596547 RCV003762896 RCV003596596 RCV003596560 RCV003596575 RCV003596573 RCV003596622 RCV003596599 RCV003762969 RCV003763753 RCV003595676 RCV003763771 RCV003595661 RCV003595710 RCV003595709 RCV003595718 RCV003763906 RCV003763924 RCV003595733	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Increased circulating IgE concentration	Likely pathogenic; Pathogenic	rs368134354, rs752941297	RCV000414954 RCV000415446	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Netherton syndrome	Pathogenic; Likely pathogenic	rs750225476, rs375224787, rs1752708600, rs1753640069, rs192473445, rs201674667, rs750789505, rs776293648, rs121908387, rs587777749, rs565782662, rs1754222214, rs201269335, rs748978134, rs773514258, rs199757347, rs766754092, rs1057518161, rs368134354, rs775341740, rs752941297, rs756874525, rs1131691490, rs373463881, rs766978225, rs752179828, rs761490126, rs367958902, rs753621591, rs1561680487, rs1561695740, rs1561686960, rs1581074967, rs752777832, rs1212676320, rs1752706120, rs1753397877, rs924297783, rs1340491788, rs777436361	RCV001310294 RCV004796647 RCV001783798 RCV001837364 RCV005031901 RCV001946939 RCV004796674 RCV005038364 RCV000005582 RCV000005583 RCV000005584 RCV002776177 RCV001063839 RCV001089994 RCV003328121 RCV003328122 RCV000371796 RCV005036958 RCV004798830 RCV000766268 RCV005033940 RCV000806530 RCV005034010 RCV000794069 RCV001380051 RCV000539268 RCV004596239 RCV000604151 RCV005034201 RCV000991162 RCV000761521 RCV000766267 RCV000766269 RCV000766270 RCV005047055 RCV000800344 RCV005866771 RCV003151831 RCV005036401 RCV001229273 RCV005036507 RCV001270889	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ovarian serous cystadenocarcinoma	Likely pathogenic	rs374012512	RCV005927743	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Susceptibility to nonsyndromic otitis media	Pathogenic	rs199757347	RCV001260962	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Cholangiocarcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Colon adenocarcinoma	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DENTAL CARIES	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DESBUQUOIS SYNDROME	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ERYTHEMATOSQUAMOUS DERMATOSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant lymphoma, large B-cell, diffuse	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Otitis media, susceptibility to	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PROSTATIC NEOPLASMS	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SEBORRHEIC DERMATITIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SPINK5 POLYMORPHISM	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SPINK5-related disorder	Likely benign; Conflicting classifications of pathogenicity; Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thymoma	Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine carcinosarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
VASCULAR DEMENTIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acanthosis Nigricans	Acanthosis Nigricans	HPO_DG			★☆☆☆☆ Found in Text Mining only
Acute pancreatitis	Pancreatitis	BEFREE	16291148		★☆☆☆☆ Found in Text Mining only
Allergic rhinitis (disorder)	Allergic rhinitis	BEFREE	15370566		★☆☆☆☆ Found in Text Mining only
Allergic rhinitis (disorder)	Allergic rhinitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Asthma	Asthma	BEFREE	12752122, 14551605, 15005725, 15753894, 15820494, 19534795, 21585560, 22133475, 22570283, 24831437, 25233048, 28552993		★☆☆☆☆ Found in Text Mining only
Asthma	Asthma	Pubtator	16519819, 19534795, 24831437	Associate	★☆☆☆☆ Found in Text Mining only
Asthma	Asthma	HPO_DG			★☆☆☆☆ Found in Text Mining only
Blood Coagulation Disorders Inherited	Blood coagulation disorder	Pubtator	39501396	Associate	★☆☆☆☆ Found in Text Mining only
Brain Diseases	Brain disease	Pubtator	26732982	Associate	★☆☆☆☆ Found in Text Mining only
Carcinogenesis	Carcinogenesis	Pubtator	16670719	Associate	★☆☆☆☆ Found in Text Mining only
Carcinogenesis	Carcinogenesis	Pubtator	24763828	Stimulate	★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	26517370, 37990105	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	16670719	Associate	★☆☆☆☆ Found in Text Mining only
Childhood asthma	Asthma	BEFREE	24831437		★☆☆☆☆ Found in Text Mining only
Chronic sinusitis	Sinusitis	BEFREE	22570283		★☆☆☆☆ Found in Text Mining only
Clastothrix	Clastothrix	HPO_DG			★☆☆☆☆ Found in Text Mining only
Congenital ichthyosis	Congenital Ichthyosis	BEFREE	11857617, 15590704, 28913623, 30390391, 31255470		★☆☆☆☆ Found in Text Mining only
Congenital Nonbullous Ichthyosiform Erythroderma	Congenital Nonbullous Ichthyosiform Erythroderma	BEFREE	30801672		★☆☆☆☆ Found in Text Mining only
Congenital Nonbullous Ichthyosiform Erythroderma	Congenital Nonbullous Ichthyosiform Erythroderma	HPO_DG			★☆☆☆☆ Found in Text Mining only
Coronary Artery Disease	Coronary artery disease	Pubtator	35069582	Associate	★☆☆☆☆ Found in Text Mining only
Craniosynostosis	Craniosynostosis	BEFREE	18588753, 22570283, 27779422		★☆☆☆☆ Found in Text Mining only
Dementia	Dementia	Pubtator	26329378, 26732982, 28230174	Associate	★☆☆☆☆ Found in Text Mining only
Dermatitis	Dermatitis	Pubtator	31450277	Associate	★☆☆☆☆ Found in Text Mining only
Dermatitis Atopic	Atopic dermatitis	Pubtator	19534795, 27769847, 29926005, 31450277, 37239440	Associate	★☆☆☆☆ Found in Text Mining only
Dermatitis Atopic 1	Atopic dermatitis	Pubtator	19534795	Associate	★☆☆☆☆ Found in Text Mining only
Dermatitis, Atopic	Dermatitis	LHGDN	11796258, 14551605, 17989887		★☆☆☆☆ Found in Text Mining only
Dermatitis, Atopic	Dermatitis	BEFREE	12752122, 14551605, 15005725, 15606522, 15753894, 17989887, 19438860, 19467033, 19522716, 19534795, 21087323, 21174234, 21585560, 22017185, 22730493, 25131691, 26385242, 27769847, 31407378, 31501002		★☆☆☆☆ Found in Text Mining only
Dermatologic disorders	Dermatologic Disorders	LHGDN	11796258		★☆☆☆☆ Found in Text Mining only
Dermatologic disorders	Dermatologic Disorders	BEFREE	14551605, 15606522, 19438860		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus Type 1	Diabetes mellitus, type 1	Pubtator	35069582	Associate	★☆☆☆☆ Found in Text Mining only
Dissection of aorta	Aortic dissection	BEFREE	29525729		★☆☆☆☆ Found in Text Mining only
Dwarfism	Dwarfism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Ectopic kidney	Ectopic kidney	HPO_DG			★☆☆☆☆ Found in Text Mining only
Eczema	Eczema	BEFREE	12752122, 14551605, 15005725, 15606522, 15753894, 17989887, 18774391, 19438860, 19467033, 19522716, 19534795, 20085599, 21087323, 21174234, 21585560, 22730493, 25131691, 26385242, 27769847, 31407378, 31501002		★☆☆☆☆ Found in Text Mining only
Eczema	Eczema	HPO_DG			★☆☆☆☆ Found in Text Mining only
Eosinophilia	Eosinophilia	Pubtator	19534795	Associate	★☆☆☆☆ Found in Text Mining only
Eosinophilic esophagitis	Eosinophilia	BEFREE	25620273		★☆☆☆☆ Found in Text Mining only
Eosinophilic Esophagitis	Eosinophilia	Pubtator	28712126	Inhibit	★☆☆☆☆ Found in Text Mining only
Epilepsy	Epilepsy	Pubtator	28230174	Associate	★☆☆☆☆ Found in Text Mining only
Esophageal carcinoma	Esophageal Carcinoma	BEFREE	30868765		★☆☆☆☆ Found in Text Mining only
Esophageal Neoplasms	Esophagus Neoplasm	BEFREE	30868765		★☆☆☆☆ Found in Text Mining only
Essential Tremor	Essential tremor	Pubtator	36183486	Associate	★☆☆☆☆ Found in Text Mining only
Exfoliative dermatitis	Exfoliative Dermatitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Exfoliative dermatitis	Exfoliative Dermatitis	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Global developmental delay	Developmental Delay	HPO_DG			★☆☆☆☆ Found in Text Mining only
Growth Disorders	Growth disorder	Pubtator	17989726	Associate	★☆☆☆☆ Found in Text Mining only
Hydronephrosis	Hydronephrosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypereosinophilia	Hypereosinophilia	BEFREE	19534795		★☆☆☆☆ Found in Text Mining only
Hypereosinophilia	Hypereosinophilia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypersensitivity Immediate	Hypersensitivity	Pubtator	21997416	Associate	★☆☆☆☆ Found in Text Mining only
Ichthyoses	Ichthyosis	BEFREE	11857617, 15590704, 28913623, 30390391, 31255470		★☆☆☆☆ Found in Text Mining only
Ichthyosiform Erythroderma, Congenital	Ichthyosis Congenita	BEFREE	15347338, 15606522, 17989726		★☆☆☆☆ Found in Text Mining only
Ichthyosis	Ichthyosis	Pubtator	29926005, 33807935	Associate	★☆☆☆☆ Found in Text Mining only
Ichthyosis Lamellar	Lamellar ichthyosis	Pubtator	11874482, 17989726, 25526335	Associate	★☆☆☆☆ Found in Text Mining only
Ichthyosis linearis circumflexa	Netherton syndrome	BEFREE	10835624, 11511292, 11841556, 11857617, 11874482, 11943586, 12915442, 12923596, 14551605, 15304086, 15347338, 15590704, 15606522, 15656819, 15675955, 15780751, 15942217, 16120162, 16225619, 16291148, 16374478, 16601670, 16628198, 17608759, 17989726, 19438860, 19467033, 19534795, 19683336, 20877344, 21174234, 21564178, 21585560, 21692842, 22089833, 22377713, 22730493, 23331056, 23344365, 23407075, 24015757, 24329107, 24506793, 24848304, 25665175, 26825155, 26865388, 27905021, 28095415, 30270115, 30477583, 30801672, 31255470		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ichthyosis linearis circumflexa	Netherton syndrome	ORPHANET_DG	10835624		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ichthyosis linearis circumflexa	Netherton syndrome	CLINVAR_DG	11511292, 11841556, 22089833, 22377713, 25665175, 26865388		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ichthyosis linearis circumflexa	Netherton syndrome	GENOMICS_ENGLAND_DG	11841556, 28289593		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ichthyosis linearis circumflexa	Netherton syndrome	CTD_human_DG	20657595		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ichthyosis, X-Linked	Ichthyosis	BEFREE	27478344		★☆☆☆☆ Found in Text Mining only
IgE RESPONSIVENESS, ATOPIC	Ige Responsiveness, Atopic	GENOMICS_ENGLAND_DG	11841556		★☆☆☆☆ Found in Text Mining only
Intellectual Disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Keratosis Linearis with Ichthyosis Congenita and Sclerosing Keratoderma	Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome	Pubtator	11841556, 25526335, 25710899, 31450277	Associate	★☆☆☆☆ Found in Text Mining only
Leukemia	Leukemia	Pubtator	27374947	Associate	★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus Systemic	Systemic lupus erythematosus	Pubtator	16519819	Associate	★☆☆☆☆ Found in Text Mining only
Lymphatic Metastasis	Lymphatic metastasis	Pubtator	35368958	Associate	★☆☆☆☆ Found in Text Mining only
Malabsorption Syndrome	Malabsorption Syndrome	HPO_DG			★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of esophagus	Esophagus Neoplasm	BEFREE	30868765		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	CTD_human_DG	17013881		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	28125617		★☆☆☆☆ Found in Text Mining only
Mouth Neoplasms	Mouth neoplasm	Pubtator	25029526	Associate	★☆☆☆☆ Found in Text Mining only
Nasal Polyps	Nasal polyposis	BEFREE	18588753, 22570283		★☆☆☆☆ Found in Text Mining only
Nasal Polyps	Nasal polyp	Pubtator	18588753	Inhibit	★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	30868765		★☆☆☆☆ Found in Text Mining only
Netherton syndrome	Netherton Syndrome	Orphanet			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Neurodegenerative Diseases	Neurodegenerative disorder	Pubtator	26329378	Associate	★☆☆☆☆ Found in Text Mining only
Parakeratosis	Parakeratosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
PEELING SKIN SYNDROME	Peeling Skin Syndrome	BEFREE	15942217		★☆☆☆☆ Found in Text Mining only
Peeling Skin Syndrome	Peeling skin syndrome	Pubtator	30032785	Associate	★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic Neoplasms	CTD_human_DG	17013881		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Psoriasis	Psoriasis	Pubtator	16519819	Associate	★☆☆☆☆ Found in Text Mining only
Psoriasis	Psoriasis	BEFREE	31501002		★☆☆☆☆ Found in Text Mining only
Rhinitis Allergic	Rhinitis	Pubtator	19534795	Associate	★☆☆☆☆ Found in Text Mining only
Rosacea	Rosacea	Pubtator	30270115	Stimulate	★☆☆☆☆ Found in Text Mining only
Skin Diseases	Skin disease	Pubtator	19534795, 22936986, 36569942	Associate	★☆☆☆☆ Found in Text Mining only
Skin Diseases	Skin disease	Pubtator	31501002	Stimulate	★☆☆☆☆ Found in Text Mining only
Skin Diseases Genetic	Skin disease	Pubtator	16374478	Associate	★☆☆☆☆ Found in Text Mining only
Skin lesion	Skin Lesion	BEFREE	31501002		★☆☆☆☆ Found in Text Mining only
Spondyloepiphyseal dysplasia Omani type	Spondyloepiphyseal dysplasia	Pubtator	34888090	Associate	★☆☆☆☆ Found in Text Mining only
Squamous cell carcinoma	Carcinoma	LHGDN	15680911		★☆☆☆☆ Found in Text Mining only
Squamous cell carcinoma	Carcinoma	BEFREE	30226546		★☆☆☆☆ Found in Text Mining only
Squamous Cell Carcinoma of Head and Neck	Squamous cell carcinoma	Pubtator	18254958	Inhibit	★☆☆☆☆ Found in Text Mining only
Squamous Cell Carcinoma of Head and Neck	Squamous cell carcinoma	Pubtator	21443540, 30226546, 37185487	Associate	★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	24763828	Associate	★☆☆☆☆ Found in Text Mining only
Trichohepatoenteric Syndrome	Trichohepatoenteric Syndrome	BEFREE	23347305		★☆☆☆☆ Found in Text Mining only
Trichorrhexis nodosa syndrome	Trichorrhexis nodosa syndrome	Pubtator	11841556, 31450277	Associate	★☆☆☆☆ Found in Text Mining only
Urticaria	Urticaria	HPO_DG			★☆☆☆☆ Found in Text Mining only