SYNE4 (spectrin repeat containing nuclear envelope family member 4)

Gene

• Entrez ID: 163183
• Gene name: Spectrin repeat containing nuclear envelope family member 4
• Gene symbol: SYNE4
• Synonyms (NCBI Gene): C19orf46, DFNB76, KASH4, Nesp4
• Chromosome: 19
• Chromosome location: 19q13.12
• Summary: This gene is a member of the nesprin family of genes, that encode KASH (Klarsicht, Anc-1, Syne Homology) domain-containing proteins. In addition to the KASH domain, this protein also contains a coiled-coil and leucine zipper region, a spectrin repeat, and

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs141202530	C>G,T	Conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant
rs200484521	C>T	Likely-pathogenic	Coding sequence variant, stop gained
rs587777072	AT>-	Pathogenic	Frameshift variant, coding sequence variant
rs750797779	G>A	Likely-pathogenic	Stop gained, coding sequence variant, intron variant
rs758800042	->TC	Pathogenic	Frameshift variant, coding sequence variant
rs774276326	C>T	Conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant
rs1555785625	GCCCAGGCCCTGGGCT>-	Pathogenic	Intron variant, coding sequence variant, frameshift variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005515	Function	Protein binding	IPI	21516116, 25416956, 25910212, 26871637, 31515488, 32296183, 32814053, 33058875, 33393904, 33961781
GO:0005634	Component	Nucleus	IEA
GO:0005635	Component	Nuclear envelope	IEA
GO:0005640	Component	Nuclear outer membrane	IBA
GO:0005640	Component	Nuclear outer membrane	IEA
GO:0005640	Component	Nuclear outer membrane	ISS
GO:0016020	Component	Membrane	IEA
GO:0034993	Component	Meiotic nuclear membrane microtubule tethering complex	IEA
GO:0045198	Process	Establishment of epithelial cell apical/basal polarity	IBA
GO:0045198	Process	Establishment of epithelial cell apical/basal polarity	IEA
GO:0045198	Process	Establishment of epithelial cell apical/basal polarity	ISS

Other IDs

• MIM: 615535
• HGNC: 26703
• e!Ensembl: ENSG00000181392

Protein

• UniProt ID: Q8N205
• Protein name: Nesprin-4 (KASH domain-containing protein 4) (KASH4) (Nuclear envelope spectrin repeat protein 4)
• Protein function: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role
• PDB: 6R16, 6WMD
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF10541	KASH	349 → 404	Nuclear envelope localisation domain	Domain

• Sequence:

  MALSLPLGPRLGSEPLNHPPGAPREADIVGCTVCPASGEESTSPEQAQTLGQDSLGPPEH
  FQGGPRGNEPAAHPPRWSTPSSYEDPAGGKHCEHPISGLEVLEAEQNSLHLCLLGLGRRL
  QDLEQGLGHWALAQSGMVQLQALQVDLRGAAERVEALLAFGEGLAQRSEPRAWAALEQIL
  RALGAYRDSIFRRLWQLQAQLVSYSLVFEEANTLDQDLEVEGDSDWPGPGGVWGPWAPSS
  LPTSTELEWDPAGDIGGLGPLGQKTARTLGVPCELCGQRGPQGRGQGLEEADTSHSRQDM
  LESGLGHQKRLARHQRHSLLRKPQDKKRQASPHLQDVRLEGNPGAPDPASRQPLTFLLIL
  FLLFLLLVGAMFLLPASGGPCCSHARIPRTPYLVLSYVNGLPPV

• Sequence length: 404

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
Autosomal recessive nonsyndromic hearing loss 76	Likely pathogenic; Pathogenic	rs754343113, rs2514041516, rs750797779, rs2514038071, rs368669131, rs2145346614, rs776772746, rs2514051953, rs772404105, rs748326281, rs758800042, rs587777072	RCV005016782 RCV005017203 RCV005025348 RCV005029926 RCV003155585 RCV005022027 RCV005014917 RCV005015042 RCV005030316 RCV005015075 RCV005019028 RCV000074459	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Nonsyndromic genetic hearing loss	Likely pathogenic; Pathogenic	rs2514041516, rs2514038071, rs2514026839, rs766580479	RCV002308678 RCV003155796 RCV005406652 RCV004783122	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Ovarian serous cystadenocarcinoma	Likely pathogenic	rs748326281	RCV005936608	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Rare genetic deafness	Likely pathogenic; Pathogenic	rs750797779	RCV000213729	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
AUTOSOMAL RECESSIVE ISOLATED SENSORINEURAL DEAFNESS TYPE DFNB	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEAFNESS, AUTOSOMAL RECESSIVE	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEAFNESS, AUTOSOMAL RECESSIVE 76	—	CTD, Disgenet, HPO CTD, Disgenet, HPO CTD, Disgenet, HPO	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial cancer of breast	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HEARING LOSS, AUTOSOMAL RECESSIVE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SENSORINEURAL HEARING LOSS OF BILATERAL EARS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SYNE4-related disorder	Likely benign; Benign; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SYNE4-related hearing loss	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Autosomal recessive non-syndromic sensorineural deafness type DFNB	Non-Syndromic Sensorineural Deafness	Orphanet			★☆☆☆☆ Found in Text Mining only
Deafness	Deafness	Pubtator	35682719	Associate	★☆☆☆☆ Found in Text Mining only
DEAFNESS, AUTOSOMAL RECESSIVE 76	Deafness	GENOMICS_ENGLAND_DG	28958982		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEAFNESS, AUTOSOMAL RECESSIVE 76	Deafness	CLINVAR_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEAFNESS, AUTOSOMAL RECESSIVE 76	Deafness	CTD_human_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hearing Loss	Hearing loss	Pubtator	28958982, 35682719	Associate	★☆☆☆☆ Found in Text Mining only
Hearing Loss Sensorineural	Hearing loss	Pubtator	28958982	Associate	★☆☆☆☆ Found in Text Mining only
Hearing Loss, High-Frequency	Hearing Loss	BEFREE	23348741		★☆☆☆☆ Found in Text Mining only
Nonsyndromic Deafness	Nonsyndromic Deafness	CLINGEN_DG	23348741		★☆☆☆☆ Found in Text Mining only