7-138706689-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020632.3(ATP6V0A4):c.2458G>A(p.Gly820Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.73

Variant links:

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) 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]

ATP6V0A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP6V0A4	NM_020632.3 linkuse as main transcript	c.2458G>A	p.Gly820Arg	missense_variant	22/22	ENST00000310018.7
ATP6V0A4	NM_130840.3 linkuse as main transcript	c.2458G>A	p.Gly820Arg	missense_variant	21/21
ATP6V0A4	NM_130841.3 linkuse as main transcript	c.2458G>A	p.Gly820Arg	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7 linkuse as main transcript	c.2458G>A	p.Gly820Arg	missense_variant	22/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251316

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000980

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 820 of the ATP6V0A4 protein (p.Gly820Arg). This variant is present in population databases (rs267606671, gnomAD 0.01%). This missense change has been observed in individual(s) with distal renal tubular acidosis (PMID: 10973252). ClinVar contains an entry for this variant (Variation ID: 5151). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP6V0A4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP6V0A4 function (PMID: 18632794, 29311258). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.47

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D;D;.;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;H;.;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.7

D;D;.;.;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.;.;D

Sift4G

Pathogenic

0.0

D;D;.;.;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.85

MutPred

0.96

Gain of methylation at G820 (P = 0.0186);Gain of methylation at G820 (P = 0.0186);Gain of methylation at G820 (P = 0.0186);.;Gain of methylation at G820 (P = 0.0186);

MVP

0.99

MPC

0.84

ClinPred

1.0

GERP RS

4.9

Varity_R

0.82

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over