SLC9A3 (solute carrier family 9 member A3)

Gene

• Entrez ID: 6550
• Gene name: Solute carrier family 9 member A3
• Gene symbol: SLC9A3
• Synonyms (NCBI Gene): DIAR8, NHE-3, NHE3
• Chromosome: 5
• Chromosome location: 5p15.33
• Summary: The protein encoded by this gene is an epithelial brush border Na/H exchanger that uses an inward sodium ion gradient to expel acids from the cell. Defects in this gene are a cause of congenital secretory sodium diarrhea. Pseudogenes of this gene exist on

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs144524702	C>T	Likely-pathogenic	Splice donor variant
rs766076524	C>T	Pathogenic	Coding sequence variant, missense variant
rs766583286	C>T	Likely-pathogenic	Coding sequence variant, missense variant
rs776026092	AGA>-	Pathogenic	Coding sequence variant, inframe deletion
rs869312806	G>A	Pathogenic	Coding sequence variant, missense variant
rs869312807	C>T	Pathogenic	Coding sequence variant, missense variant
rs869320759	->C	Pathogenic	Coding sequence variant, frameshift variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT490730	hsa-miR-132-5p	PAR-CLIP	23592263
MIRT490729	hsa-miR-6786-5p	PAR-CLIP	23592263
MIRT490728	hsa-miR-2277-3p	PAR-CLIP	23592263
MIRT490727	hsa-miR-2277-5p	PAR-CLIP	23592263
MIRT490726	hsa-miR-1199-3p	PAR-CLIP	23592263
MIRT490725	hsa-miR-3960	PAR-CLIP	23592263
MIRT490724	hsa-miR-8072	PAR-CLIP	23592263
MIRT490723	hsa-miR-4706	PAR-CLIP	23592263
MIRT490722	hsa-miR-4749-5p	PAR-CLIP	23592263
MIRT490720	hsa-miR-4634	PAR-CLIP	23592263
MIRT490721	hsa-miR-4467	PAR-CLIP	23592263
MIRT490719	hsa-miR-3191-3p	PAR-CLIP	23592263
MIRT490718	hsa-miR-541-3p	PAR-CLIP	23592263
MIRT490717	hsa-miR-654-5p	PAR-CLIP	23592263
MIRT490716	hsa-miR-1302	PAR-CLIP	23592263
MIRT490715	hsa-miR-4298	PAR-CLIP	23592263
MIRT490714	hsa-miR-1228-5p	PAR-CLIP	23592263
MIRT490730	hsa-miR-132-5p	PAR-CLIP	23592263
MIRT490729	hsa-miR-6786-5p	PAR-CLIP	23592263
MIRT490728	hsa-miR-2277-3p	PAR-CLIP	23592263
MIRT490727	hsa-miR-2277-5p	PAR-CLIP	23592263
MIRT490726	hsa-miR-1199-3p	PAR-CLIP	23592263
MIRT490725	hsa-miR-3960	PAR-CLIP	23592263
MIRT490724	hsa-miR-8072	PAR-CLIP	23592263
MIRT490723	hsa-miR-4706	PAR-CLIP	23592263
MIRT490722	hsa-miR-4749-5p	PAR-CLIP	23592263
MIRT490720	hsa-miR-4634	PAR-CLIP	23592263
MIRT490721	hsa-miR-4467	PAR-CLIP	23592263
MIRT490719	hsa-miR-3191-3p	PAR-CLIP	23592263
MIRT490718	hsa-miR-541-3p	PAR-CLIP	23592263
MIRT490717	hsa-miR-654-5p	PAR-CLIP	23592263
MIRT490716	hsa-miR-1302	PAR-CLIP	23592263
MIRT490715	hsa-miR-4298	PAR-CLIP	23592263
MIRT490714	hsa-miR-1228-5p	PAR-CLIP	23592263

Transcription factors

Transcription factor	Regulation	Reference
EGR1	Activation	16464174

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005515	Function	Protein binding	IPI	16159897, 19088451, 25851603, 35613257
GO:0005768	Component	Endosome	IEA
GO:0005769	Component	Early endosome	IDA	25851603
GO:0005886	Component	Plasma membrane	IBA
GO:0005886	Component	Plasma membrane	IDA	26358773, 35613257
GO:0005886	Component	Plasma membrane	IEA
GO:0005886	Component	Plasma membrane	ISS
GO:0005886	Component	Plasma membrane	TAS
GO:0005903	Component	Brush border	ISS
GO:0006811	Process	Monoatomic ion transport	IEA
GO:0006811	Process	Monoatomic ion transport	TAS
GO:0006812	Process	Monoatomic cation transport	IEA
GO:0006814	Process	Sodium ion transport	IEA
GO:0006885	Process	Regulation of pH	IEA
GO:0009986	Component	Cell surface	ISS
GO:0015297	Function	Antiporter activity	IEA
GO:0015385	Function	Sodium:proton antiporter activity	IBA
GO:0015385	Function	Sodium:proton antiporter activity	IDA	26358773
GO:0015385	Function	Sodium:proton antiporter activity	IEA
GO:0015385	Function	Sodium:proton antiporter activity	ISS
GO:0015385	Function	Sodium:proton antiporter activity	TAS
GO:0015386	Function	Potassium:proton antiporter activity	IBA
GO:0016020	Component	Membrane	IEA
GO:0016324	Component	Apical plasma membrane	IBA
GO:0016324	Component	Apical plasma membrane	IEA
GO:0016324	Component	Apical plasma membrane	ISS
GO:0030165	Function	PDZ domain binding	ISS
GO:0031526	Component	Brush border membrane	IBA
GO:0031526	Component	Brush border membrane	ISS
GO:0031901	Component	Early endosome membrane	IEA
GO:0035091	Function	Phosphatidylinositol binding	IDA	35613257
GO:0042802	Function	Identical protein binding	IDA	35613257
GO:0051453	Process	Regulation of intracellular pH	IBA
GO:0051453	Process	Regulation of intracellular pH	IDA	35613257
GO:0055038	Component	Recycling endosome membrane	IDA	35613257
GO:0055038	Component	Recycling endosome membrane	IEA
GO:0055085	Process	Transmembrane transport	IEA
GO:0070062	Component	Extracellular exosome	HDA	19056867
GO:0070062	Component	Extracellular exosome	IDA	16501490
GO:0071805	Process	Potassium ion transmembrane transport	IBA
GO:0098719	Process	Sodium ion import across plasma membrane	IBA
GO:0098719	Process	Sodium ion import across plasma membrane	IDA	26358773
GO:1902600	Process	Proton transmembrane transport	IEA

Other IDs

• MIM: 182307
• HGNC: 11073
• e!Ensembl: ENSG00000066230

Protein

• UniProt ID: P48764
• Protein name: Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3) (NHE-3) (Solute carrier family 9 member 3)
• Protein function: Plasma membrane Na(+)/H(+) antiporter (PubMed:18829453, PubMed:26358773, PubMed:35613257). Exchanges intracellular H(+) ions for extracellular Na(+) in 1:1 stoichiometry, playing a key role in salt and fluid absorption and pH homeostasis (By sim
• PDB: 7X2U
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00999	Na_H_Exchanger	58 → 462	Sodium/hydrogen exchanger family	Family

• Sequence:

  MWGLGARGPDRGLLLALALGGLARAGGVEVEPGGAHGESGGFQVVTFEWAHVQDPYVIAL
  WILVASLAKIGFHLSHKVTSVVPESALLIVLGLVLGGIVWAADHIASFTLTPTVFFFYLL
  PPIVLDAGYFMPNRLFFGNLGTILLYAVVGTVWNAATTGLSLYGVFLSGLMGDLQIGLLD
  FLLFGSLMAAVDPVAVLAVFEEVHVNEVLFIIVFGESLLNDAVTVVLYNVFESFVALGGD
  NVTGVDCVKGIVSFFVVSLGGTLVGVVFAFLLSLVTRFTKHVRIIEPGFVFIISYLSYLT
  SEMLSLSAILAITFCGICCQKYVKANISEQSATTVRYTMKMLASSAETIIFMFLGISAVN
  PFIWTWNTAFVLLTLVFISVYRAIGVVLQTWLLNRYRMVQLEPIDQVVLSYGGLRGAVAF
  ALVVLLDGDKVKEKNLFVSTTIIVVFFTVIFQGLTIKPLVQWLKVKRSEHREPRLNEKLH
  GRAFDHILSAIEDISGQIGHNYLRDKWSHFDRKFLSRVLMRRSAQKSRDRILNVFHELNL
  KDAISYVAEGERRGSLAFIRSPSTDNVVNVDFTPRSSTVEASVSYLLRENVSAVCLDMQS
  LEQRRRSIRDAEDMVTHHTLQQYLYKPRQEYKHLYSRHELTPTEDEKQDREIFHRTMRKR
  LESFKSTKLGLNQNKKAAKLYKRERAQKRRNSSIPNGKLPMESPAQNFTIKEKDLELSDT
  EEPPNYDEEMSGGIEFLASVTKDTASDSPAGIDNPVFSPDEALDRSLLARLPPWLSPGET
  VVPSQRARTQIPYSPGTFCRLMPFRLSSKSVDSFLQADGPEERPPAALPESTHM

• Sequence length: 834

Pathways

KEGG:

Proximal tubule bicarbonate reclamation
Protein digestion and absorption
Bile secretion
Mineral absorption

Reactome:

Sodium/Proton exchangers

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
Congenital secretory sodium diarrhea 8	Pathogenic; Likely pathogenic	rs869312806, rs776026092, rs766076524, rs869320692, rs869312807, rs869320759, rs144524702, rs766583286, rs1447447724	RCV000210219 RCV000210210 RCV000210215 RCV000210220 RCV000210211 RCV000210218 RCV000723302 RCV000767856 RCV001267641	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Autism spectrum disorder	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
AUTISM SPECTRUM DISORDERS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL SECRETORY DIARRHEA, SODIUM TYPE	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CONGENITAL SODIUM DIARRHEA	—	Disgenet, Orphanet Disgenet, Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CYSTIC FIBROSIS	—	Disgenet, GWAS catalog, Orphanet Disgenet, GWAS catalog, Orphanet Disgenet, GWAS catalog, Orphanet Disgenet, GWAS catalog, Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CYSTIC FIBROSIS, MODIFIER OF, 1	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIABETES MELLITUS, EXPERIMENTAL	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIARRHEA	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIVERTICULAR DISEASE	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DYSENTERY	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
EDEMA	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial cancer of breast	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HYPOTENSION	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INTESTINAL OBSTRUCTION	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
LUNG DISEASE ASSOCIATED WITH CYSTIC FIBROSIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Schizophrenia	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
SLC9A3-related disorder	Likely benign; Benign; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine carcinosarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acute Kidney Tubular Necrosis	Renal tubular necrosis	BEFREE	23324582		★☆☆☆☆ Found in Text Mining only
Adenoma	Adenoma	LHGDN	19056765		★☆☆☆☆ Found in Text Mining only
Anemia	Anemia	BEFREE	27390324		★☆☆☆☆ Found in Text Mining only
Azoospermia	Azoospermia	BEFREE	28384194		★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	26218645	Associate	★☆☆☆☆ Found in Text Mining only
Cardiovascular Diseases	Cardiovascular disease	Pubtator	28495802	Associate	★☆☆☆☆ Found in Text Mining only
Central Diabetes Insipidus	Diabetes Insipidus	BEFREE	25552580, 29597352		★☆☆☆☆ Found in Text Mining only
Cholelithiasis	Cholecystolithiasis	Pubtator	25674247	Associate	★☆☆☆☆ Found in Text Mining only
Chronic kidney disease stage 5	Kidney Disease	BEFREE	10642288, 31677150		★☆☆☆☆ Found in Text Mining only
Chronic Kidney Diseases	Kidney Disease	BEFREE	28432691, 31677150		★☆☆☆☆ Found in Text Mining only
Colitis	Colitis	BEFREE	25271043, 29875400		★☆☆☆☆ Found in Text Mining only
Colitis Collagenous	Collagenous colitis	Pubtator	33930606	Associate	★☆☆☆☆ Found in Text Mining only
Colitis Ulcerative	Ulcerative colitis	Pubtator	12181169	Associate	★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	BEFREE	26358773, 31276831		★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	UNIPROT_DG	26358773		★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	GENOMICS_ENGLAND_DG	26358773		★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	ORPHANET_DG	26358773		★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Congenital secretory diarrhea, sodium type (disorder)	Congenital secretory diarrhea	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Congestive heart failure	Congestive Heart Failure	BEFREE	29038209, 30640740, 31490733		★☆☆☆☆ Found in Text Mining only
Coronary Disease	Coronary artery disease	Pubtator	28629174	Associate	★☆☆☆☆ Found in Text Mining only
Coronary heart disease	Coronary Heart Disease	BEFREE	28629174		★☆☆☆☆ Found in Text Mining only
Cyst	Cyst	BEFREE	31570523		★☆☆☆☆ Found in Text Mining only
Cystic Disease Of Lung	Cystic lung disease	Pubtator	26140448	Associate	★☆☆☆☆ Found in Text Mining only
Cystic Fibrosis	Cystic Fibrosis	BEFREE	16421216, 20967843, 25771386, 26140448, 26417704, 28384194, 28756021, 29635781, 30118317		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cystic Fibrosis	Cystic fibrosis	Pubtator	25771386, 36921087	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cystic Fibrosis	Cystic Fibrosis	GWASCAT_DG	26417704		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
CYSTIC FIBROSIS MODIFIER 1	Cystic Fibrosis	CTD_human_DG	22466613		★☆☆☆☆ Found in Text Mining only
Deep Vein Thrombosis	Thrombosis	BEFREE	29864786		★☆☆☆☆ Found in Text Mining only
Dent disease type 1	Dent`s Disease	BEFREE	31472005		★☆☆☆☆ Found in Text Mining only
Diabetes	Diabetes	BEFREE	23370527, 26258413, 29227582, 31166707		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus	Diabetes Mellitus	BEFREE	23370527, 26258413, 29227582, 31166707		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	BEFREE	29110392		★☆☆☆☆ Found in Text Mining only
Diarrhea	Diarrhea	Pubtator	12181169, 28882825, 35775128	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Diarrhea 3 Secretory Sodium Congenital	Congenital secretory diarrhea	Pubtator	26358773, 28407399, 35775128	Associate	★☆☆☆☆ Found in Text Mining only
Dysentery	Dysentery	Pubtator	28495802	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Eosinophilic esophagitis	Eosinophilia	BEFREE	29729938		★☆☆☆☆ Found in Text Mining only
Eosinophilic Esophagitis	Eosinophilia	Pubtator	29729938	Associate	★☆☆☆☆ Found in Text Mining only
Gastroesophageal Reflux	Gastroesophageal reflux disease	Pubtator	26337663	Associate	★☆☆☆☆ Found in Text Mining only
Gastroschisis	Gastroschisis	Pubtator	31075877	Associate	★☆☆☆☆ Found in Text Mining only
Heart Diseases	Heart disease	Pubtator	28495802	Associate	★☆☆☆☆ Found in Text Mining only
Heart failure	Heart Failure	BEFREE	29038209, 30640740		★☆☆☆☆ Found in Text Mining only
Hypernatriuria	Hypernatriuria	BEFREE	30050465		★☆☆☆☆ Found in Text Mining only
Hyperphosphatemia (disorder)	Hyperphosphatemia	BEFREE	28432691, 31677150		★☆☆☆☆ Found in Text Mining only
Hypertension	Hypertension	Pubtator	10886567	Associate	★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	BEFREE	15201541, 19654544, 21143427, 27993957, 28490531, 29626530, 30849009, 30864843, 31039655, 31352824		★☆☆☆☆ Found in Text Mining only
Hypophosphatemic Rickets, X-Linked Dominant	Hypophosphatemic Rickets	BEFREE	29126251		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory bowel disease	Pubtator	16760259, 28882825	Inhibit	★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory Bowel Disease	BEFREE	26358773, 26835907, 28882825, 29167115, 29875400		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory bowel disease	Pubtator	26358773	Associate	★☆☆☆☆ Found in Text Mining only
Intestinal Diseases	Intestinal Diseases	BEFREE	20967843		★☆☆☆☆ Found in Text Mining only
Intestinal Obstruction	Intestinal Obstruction	CTD_human_DG	22466613		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Kidney Diseases	Kidney Disease	BEFREE	28495802		★☆☆☆☆ Found in Text Mining only
Kidney Failure, Acute	Kidney Failure	BEFREE	23324582		★☆☆☆☆ Found in Text Mining only
Kidney Failure, Chronic	Kidney Failure	BEFREE	10642288, 31677150		★☆☆☆☆ Found in Text Mining only
Lung diseases	Lung Diseases	BEFREE	20967843, 24057835, 26140448		★☆☆☆☆ Found in Text Mining only
Lung Diseases	Lung disease	Pubtator	36921087	Associate	★☆☆☆☆ Found in Text Mining only
Lymphedema	Lymphedema	Pubtator	35775128	Associate	★☆☆☆☆ Found in Text Mining only
Meconium ileus	Meconium ileus	BEFREE	24057835		★☆☆☆☆ Found in Text Mining only
Microvillus inclusion disease	Microvillus Inclusion Disease	BEFREE	27229121		★☆☆☆☆ Found in Text Mining only
Microvillus inclusion disease	Microvillus inclusion disease	Pubtator	27229121	Inhibit	★☆☆☆☆ Found in Text Mining only
Microvillus inclusion disease	Microvillus inclusion disease	Pubtator	28407399	Associate	★☆☆☆☆ Found in Text Mining only
Nasal Polyps	Nasal polyposis	BEFREE	12542207		★☆☆☆☆ Found in Text Mining only
Obstructive azoospermia	Obstructive azoospermia	BEFREE	28384194, 30797621, 30956978		★☆☆☆☆ Found in Text Mining only
Renal Tubular Acidosis, Type II	Renal Tubular Acidosis	BEFREE	12027212		★☆☆☆☆ Found in Text Mining only
Sarcoma	Sarcoma	BEFREE	31748650		★☆☆☆☆ Found in Text Mining only
Spermatocele	Spermatocele	BEFREE	16421216		★☆☆☆☆ Found in Text Mining only
Trichohepatoenteric Syndrome	Trichohepatoenteric syndrome	Pubtator	20176027	Associate	★☆☆☆☆ Found in Text Mining only
Ulcerative Colitis	Ulcerative colitis	BEFREE	12181169, 20027604		★☆☆☆☆ Found in Text Mining only