SLC4A3

protein-coding

solute carrier family 4 member 3, the group of Solute carrier family 4

Gene summary

The protein encoded by this gene is a plasma membrane anion exchange protein. The encoded protein has been found in brain, heart, kidney, small intestine, and lung. [provided by RefSeq, May 2016]

MANE transcript

NM_005070.4

Inheritance

ClinVar variants

P:2U:230B:46

Top phenotype

Short QT syndrome 7

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr2:219,627,394-219,641,980

External References & Databases

Ensembl (ENSG00000114923)

Transcript & Mutation Effects

hg38 • Region Span ~14.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short QT syndrome 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859368

Submitter: PanelApp Australia

short QT syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: ClinGen

SLC4A3 encodes a plasma membrane anion exchange protein. Genetic evidence supporting SLC4A3 as a SQTS-causing gene is derived from a single publication in which exome sequencing was performed in 2 families, including one large pedigree (PMID 29167417). The same rare genetic variant (p.Arg370His, c.1109G>A) was identified in both families, suggesting they are possibly distantly related. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration. The genetic evidence, including the unbiased gene discovery approach of whole exome sequencing and segregation of the identified genetic variant with a large number of affected individuals within the presented pedigree, was considered strong. However, lack of other publications supporting this gene-disease relationship led to a score in the “moderate” range using the gene curation template. The Expert Panel discussed upgrading the final classification but was divided on this issue with 4 panelists voting for “strong” and 5 for “moderate”.

autosomal dominant distal renal tubular acidosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008368

Submitter: PanelApp Australia

short QT syndrome 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859368

Submitter: Labcorp Genetics (formerly Invitae)

short QT syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: G2P

short QT syndrome 7MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859368

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Short QT syndrome 7AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: The condition includes increased risk of arrhythmia, cardiomyopathy, and adverse cardiac outcomes, and identification may enable interventions

Refs: 29167417

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC4A3 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 200

not specifiedTotal: 52

not providedTotal: 46

SLC4A3-related disorderTotal: 21

Short QT syndrome 7Total: 9

Cardiovascular phenotypeTotal: 3

Incidental DiscoveryTotal: 1

CardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005070.4. 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			5 clinvar	25 clinvar	9 clinvar	39
missense	1 clinvar	1 clinvar	222 clinvar	12 clinvar		236
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	1	230	37	9	278

Highest pathogenic variant AF is 0.0000049563223

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 128 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005070.4	RefSeq	NP_005061.3	22	MANE Select
ENST00000358055.8	Ensembl	ENSP00000350756.3	22	MANE Select
NM_001326559.2	RefSeq	NP_001313488.2	22	Standard
NM_001438863.1	RefSeq	NP_001425792.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
slc4a3	Danio rerio	Structure: heart Quality: functionality abnormal

Gene / Model

Organism

Observed Phenotype

slc4a3

Danio rerio

Structure: heart

Quality: functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transport of inorganic cations/anions and amino acids/oligopeptides
SLC-mediated transmembrane transport
Transport of small molecules
Bicarbonate transporters

Biological Process

inorganic anion transport
bicarbonate transport
regulation of intracellular pH
anion transmembrane transport

Molecular Function

inorganic anion exchanger activity
anion:anion antiporter activity

Cellular Component

plasma membrane
integral component of plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373762
Coding exons: 22
Length: 14654
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125746
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.74	571	787	0.725	0.0000513	8031
Missense (PolyPhen)		206	354.34	0.58135		3574
Synonymous	0.690	327	343	0.953	0.0000226	2730
Loss of Function	4.25	18	50.7	0.355	0.00000285	548

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00012	0.00011	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plasma membrane anion exchange protein of wide distribution. Mediates at least a part of the Cl(-)/HCO3(-) exchange in cardiac myocytes. Both BAE3 and CAE3 forms transport Cl(-).;

Recessive Scores

pRec: 0.296

Intolerance Scores

RVIS EVS: -1.18
RVIS percentile EVS: 5.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

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