ATP6V0A4

protein-coding

ATPase H+ transporting V0 subunit a4, the group of V-type ATPase subunits

Gene summary

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

Previous symbols:

ATP6N1B
ATP6N2
RTA1C

MANE transcript

NM_020632.3

Inheritance

ClinVar variants

P:99U:249B:93

Top phenotype

Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr7:138,706,294-138,799,560

External References & Databases

Ensembl (ENSG00000105929)

Transcript & Mutation Effects

hg38 • Region Span ~93.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal tubular acidosis, distal, 3, with or without sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011268

Submitter: PanelApp Australia

renal tubular acidosis, distal, 3, with or without sensorineural hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011268

Submitter: Natera

renal tubular acidosis, distal, 3, with or without sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011268

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive distal renal tubular acidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018440

Submitter: Orphanet

renal tubular acidosis, distal, 3, with or without sensorineural hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011268

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Renal tubular acidosis, distal, 3, with or without sensorineural hearing lossAR

Manifestation: Audiologic/Otolaryngologic; Renal

Intervention: Renal

Rationale: The condition can involve electrolyte abnormalities, and medical management of these (eg, with alkali replacement) can reverse most biochemical abnormalities, and may be effective, especially in severe cases, to prevent eventual renal insufficiency

Refs: 10973252; 12414817

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6V0A4 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 310

Renal tubular acidosis, distal, 3, with or without sensorineural hearing lossTotal: 224

Inborn genetic diseasesTotal: 110

Autosomal recessive distal renal tubular acidosisTotal: 83

ATP6V0A4-related disorderTotal: 52

not specifiedTotal: 48

Renal tubulopathiesTotal: 5

Distal renal tubular acidosisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020632.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		10 clinvar	76 clinvar	4 clinvar	91
missense	1 clinvar	13 clinvar	234 clinvar	12 clinvar	1 clinvar	261
nonsense	10 clinvar	15 clinvar	2 clinvar			27
start loss						0
frameshift	18 clinvar	14 clinvar				32
splice donor/acceptor (+/-2bp)	6 clinvar	21 clinvar	3 clinvar			30
Total	36	63	249	88	5	441

Highest pathogenic variant AF is 0.0003050474

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020632.3	RefSeq	NP_065683.2	20	MANE Select
ENST00000310018.7	Ensembl	ENSP00000308122.2	20	MANE Select
NM_130840.3	RefSeq	NP_570855.2	20	Standard
NM_130841.3	RefSeq	NP_570856.2	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

ossification
regulation of pH
vacuolar acidification
excretion
sensory perception of sound

Molecular Function

protein binding
proton-transporting ATPase activity, rotational mechanism
ATPase binding

Cellular Component

vacuolar proton-transporting V-type ATPase, V0 domain
lysosomal membrane
endosome
plasma membrane
endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310018
Coding exons: 20
Length: 93266
Individuals with no LoFs: 125624
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.855	408	460	0.888	0.0000272	5582
Missense (PolyPhen)		190	219.99	0.86366		2716
Synonymous	0.0807	176	177	0.992	0.0000116	1572
Loss of Function	1.53	37	48.5	0.763	0.00000292	503

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00098	0.00098	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.00049	0.00044	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.00037	0.00037	rare
South Asian	0.00052	0.00052	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the proton channel of the V-ATPase that is involved in normal vectorial acid transport into the urine by the kidney. {ECO:0000250}.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.0336
RVIS EVS: -0.17
RVIS percentile EVS: 40.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.624

Gene Damage Prediction

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