ATP6V0A1

protein-coding

ATPase H+ transporting V0 subunit a1, the group of V-type ATPase subunits|MicroRNA protein coding host genes

Gene summary

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle 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. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene encodes one of three A subunit proteins and the encoded protein is associated with clathrin-coated vesicles. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

VPP1
ATP6N1
ATP6N1A

MANE transcript

NM_001130021.3

Inheritance

AR, AD, SD

ClinVar variants

P:15U:147B:11

Top phenotype

Developmental and epileptic encephalopathy 104; Neurodevelopmental disorder with epilepsy and brain atrophy

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr17:42,458,844-42,522,582

External References & Databases

Ensembl (ENSG00000033627)

Transcript & Mutation Effects

hg38 • Region Span ~63.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with epilepsy and brain atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859265

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 104STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031021

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 104STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031021

Submitter: Ambry Genetics

neurodevelopmental disorder with epilepsy and brain atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859265

Submitter: Ambry Genetics

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 104DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0031021

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 104; Neurodevelopmental disorder with epilepsy and brain atrophyAD/AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 33833240; 34909687

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP6V0A1 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 65

Inborn genetic diseasesTotal: 62

Developmental and epileptic encephalopathy 104Total: 29

Neurodevelopmental disorder with epilepsy and brain atrophyTotal: 14

not specifiedTotal: 8

ATP6V0A1-related conditionTotal: 5

Global developmental delayTotal: 2

SeizureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130021.3. 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			4 clinvar	7 clinvar		11
missense	6 clinvar	4 clinvar	134 clinvar	4 clinvar		148
nonsense			2 clinvar			2
start loss						0
frameshift	1 clinvar	1 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	5 clinvar			8
Total	9	6	147	11	0	173

Highest pathogenic variant AF is 0.0000041106646

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 134 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001130021.3	RefSeq	NP_001123493.1	21	MANE Select
ENST00000343619.9	Ensembl	ENSP00000342951.3	21	MANE Select
NM_001130020.3	RefSeq	NP_001123492.1	20	Standard
NM_001378522.1	RefSeq	NP_001365451.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atp6v0a1a	Danio rerio	Structure: neural crest cell Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

atp6v0a1a

Danio rerio

Structure: neural crest cell

Quality: increased amount

abnormal

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

vacuolar acidification
insulin receptor signaling pathway
ATP hydrolysis coupled proton transport
regulation of macroautophagy
transferrin transport

Molecular Function

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

Cellular Component

vacuolar proton-transporting V-type ATPase, V0 domain
lysosomal membrane
Golgi apparatus
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264649
Coding exons: 20
Length: 63768
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125747
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.74	246	476	0.517	0.0000268	5562
Missense (PolyPhen)		83	223.43	0.37148		2580
Synonymous	1.04	157	174	0.900	0.00000991	1569
Loss of Function	5.56	7	49.0	0.143	0.00000300	520

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for assembly and activity of the vacuolar ATPase. Potential role in differential targeting and regulation of the enzyme for a specific organelle (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.503

Intolerance Scores

LoFtool: 0.0440
RVIS EVS: -0.69
RVIS percentile EVS: 15.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.410

Gene Damage Prediction

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