GeneBe

SLC4A4

protein-coding

solute carrier family 4 member 4, the group of Solute carrier family 4

Gene summary

This gene encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with proximal renal tubular acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

Previous symbols:
  • SLC4A5

MANE transcript

NM_001098484.3

Inheritance

AR, AD

ClinVar variants

P:15U:177B:87

Top phenotype

Renal tubular acidosis, proximal, with ocular abnormalities and impaired intellectual development

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr4:71,062,667-71,572,087

External References & Databases

Ensembl (ENSG00000080493)NCBI Gene (8671)OMIM (603345)HGNC:11030GenCCUniProt (Q9Y6R1)AlphaFoldClinVar (SLC4A4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~509.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive proximal renal tubular acidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: Natera

autosomal recessive proximal renal tubular acidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: PanelApp Australia

autosomal recessive proximal renal tubular acidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: Ambry Genetics

autosomal recessive proximal renal tubular acidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive proximal renal tubular acidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: Orphanet

autosomal recessive proximal renal tubular acidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011422

Submitter: G2P

Clinical Genomic Database (CGD)

Renal tubular acidosis, proximal, with ocular abnormalities and impaired intellectual developmentAD/AR

Manifestation: Dental; Neurologic; Ophthalmologic; Renal

Intervention: Ophthalmologic; Renal

Rationale: Medical treatment of renal tubular acidosis may be beneficial; Diagnosis may allow early treatment related to ocular anomalies, which can include glaucoma

Comments: Heterozygous variants may result in ophthalmologic anomalies (including glaucoma) and migraine susceptibility

Refs: 8142230; 10545938; 11274232; 20798035Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC4A4 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 166
Autosomal recessive proximal renal tubular acidosisTotal: 162
Inborn genetic diseasesTotal: 93
not specifiedTotal: 20
SLC4A4-related disorderTotal: 17
Combined oxidative phosphorylation defect type 24Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098484.3. 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.

EffectPLPVUSLBBSum
synonymous
13
clinvar
70
clinvar
3
clinvar
 86
missense
2
clinvar
4
clinvar
160
clinvar
13
clinvar
1
clinvar
 180
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
2
clinvar
2
clinvar
1
clinvar
 5
splice donor/acceptor (+/-2bp)
2
clinvar
3
clinvar
 5
Total510177834279

Highest pathogenic variant AF is 0.0000034229695

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001098484.3RefSeqNP_001091954.124MANE Select
ENST00000264485.11EnsemblENSP00000264485.524MANE Select
NM_001134742.2RefSeqNP_001128214.124Standard
NM_001440628.1RefSeqNP_001427557.125Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc4a4aDanio rerio

Structure: retina

Quality: distended

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Bile secretion - Homo sapiens (human)
  • Proximal tubule bicarbonate reclamation - Homo sapiens (human)
  • Pancreatic secretion - Homo sapiens (human)
  • Transport of inorganic cations/anions and amino acids/oligopeptides
  • SLC-mediated transmembrane transport

Biological Process

  • sodium ion transport
  • inorganic anion transport
  • bicarbonate transport
  • regulation of intracellular pH
  • anion transmembrane transport

Molecular Function

  • inorganic anion exchanger activity
  • protein binding
  • sodium:bicarbonate symporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • basolateral plasma membrane
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000425175
Coding exons
24
Length
384802
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
125744
p
0.0000477
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.143675800.6330.00003057245
Missense (PolyPhen)98243.590.402313003
Synonymous0.1532102130.9870.00001182090
Loss of Function5.49748.10.1450.00000232612

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish0.0000930.000092rare
European (Non-Finnish)0.0000530.000053rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH. {ECO:0000269|PubMed:10069984, ECO:0000269|PubMed:12907161, ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:16769890, ECO:0000269|PubMed:17661077, ECO:0000269|PubMed:29500354, ECO:0000269|PubMed:9235899, ECO:0000269|PubMed:9651366}.;
Disease
DISEASE: Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) [MIM:604278]: An extremely rare autosomal recessive syndrome characterized by short stature, profound proximal renal tubular acidosis, mental retardation, bilateral glaucoma, cataracts and bandkeratopathy. pRTA is due to a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. {ECO:0000269|PubMed:10545938, ECO:0000269|PubMed:15471865, ECO:0000269|PubMed:15713912, ECO:0000269|PubMed:15930088, ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:17661077}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Loss of interaction with and stimulation by CA4 is the cause of retinitis pigmentosa type 17 (RP17).;

Recessive Scores

pRec
0.321

Intolerance Scores

LoFtool
0.0198
RVIS EVS
-0.37
RVIS percentile EVS
28.2

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.740

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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