SLC9A3

protein-coding

solute carrier family 9 member A3, the group of Solute carrier family 9

Gene 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 chromosomes 10 and 22. [provided by RefSeq, Mar 2016]

Previous symbols:

NHE3

MANE transcript

NM_004174.4

Inheritance

AD, AR

ClinVar variants

P:27U:258B:320

Top phenotype

Diarrhea 8, secretory sodium, congenital

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr5:470,456-524,449

External References & Databases

Ensembl (ENSG00000066230)

Transcript & Mutation Effects

hg38 • Region Span ~54.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital sodium diarrheaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015170

Submitter: Orphanet

congenital secretory sodium diarrhea 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014808

Submitter: PanelApp Australia

congenital secretory sodium diarrhea 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014808

Submitter: Ambry Genetics

congenital secretory sodium diarrhea 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014808

Submitter: Labcorp Genetics (formerly Invitae)

cystic fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Orphanet

Clinical Genomic Database (CGD)

Diarrhea 8, secretory sodium, congenitalAR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: Individuals have been described with severe, early-onset diarrhea and related electrolyte imbalances, and awareness may allow prompt and appropriate management of nutrition and fluid balance

Refs: 3880821; 26358773; 30633106; 31276831

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC9A3 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 719

Inborn genetic diseasesTotal: 116

not specifiedTotal: 55

SLC9A3-related disorderTotal: 34

Congenital secretory sodium diarrhea 8Total: 27

Autism spectrum disorderTotal: 1

SchizophreniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004174.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	286 clinvar	10 clinvar	298
missense	3 clinvar	4 clinvar	249 clinvar	21 clinvar	3 clinvar	280
nonsense	3 clinvar		2 clinvar			5
start loss			1 clinvar			1
frameshift	8 clinvar	1 clinvar				9
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	4 clinvar			12
Total	15	12	258	307	13	605

Highest pathogenic variant AF is 0.0000093005265

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004174.4	RefSeq	NP_004165.2	17	MANE Select
ENST00000264938.8	Ensembl	ENSP00000264938.3	17	MANE Select
NM_001284351.3	RefSeq	NP_001271280.1	17	Standard
ENST00000514375.1	Ensembl	ENSP00000422983.1	17	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc9a3.2	Danio rerio	Structure: NCC ionocyte Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

slc9a3.2

Danio rerio

Structure: NCC ionocyte

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Bile secretion - Homo sapiens (human)
Proximal tubule bicarbonate reclamation - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
Beta-agonist/Beta-blocker Pathway, Pharmacodynamics

Biological Process

ion transport
regulation of intracellular pH
potassium ion transmembrane transport
sodium ion import across plasma membrane
proton transmembrane transport

Molecular Function

protein binding
sodium:proton antiporter activity
potassium:proton antiporter activity
PDZ domain binding

Cellular Component

plasma membrane
brush border
cell surface
integral component of membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264938
Coding exons: 17
Length: 51023
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125708
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.49	365	526	0.694	0.0000349	5322
Missense (PolyPhen)		105	213.81	0.49109		2034
Synonymous	-2.05	288	247	1.17	0.0000188	1731
Loss of Function	4.83	6	38.2	0.157	0.00000216	393

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000050	0.000046	rare
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.000035	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient (PubMed:26358773). Plays an important role in signal transduction. {ECO:0000269|PubMed:26358773}.;
Disease: DISEASE: Diarrhea 8, secretory sodium, congenital (DIAR8) [MIM:616868]: A disease characterized by watery secretory diarrhea with prenatal onset, prominent abdominal distension after birth due to dilated fluid-filled loops of intestine, elevated fecal sodium concentrations and low urinary sodium concentrations. {ECO:0000269|PubMed:26358773}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0991

Intolerance Scores

LoFtool: 0.169
RVIS EVS: -1.79
RVIS percentile EVS: 2.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.686

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium