chr7-138771243-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020632.3(ATP6V0A4):c.5T>C(p.Val2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,612,452 control chromosomes in the GnomAD database, including 417,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.72 ( 39285 hom., cov: 31)

Exomes 𝑓: 0.72 ( 378659 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.12

Publications

44 publications found

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 Gene-Disease associations (from GenCC):

renal tubular acidosis, distal, 3, with or without sensorineural hearing loss
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive distal renal tubular acidosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATP6V0A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.507831E-7).

BP6

Variant 7-138771243-A-G is Benign according to our data. Variant chr7-138771243-A-G is described in ClinVar as [Benign]. Clinvar id is 261345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3 link	c.5T>C	p.Val2Ala	missense_variant	Exon 3 of 22	ENST00000310018.7	NP_065683.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130840.3 link	c.5T>C	p.Val2Ala	missense_variant	Exon 2 of 21		NP_570855.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130841.3 link	c.5T>C	p.Val2Ala	missense_variant	Exon 2 of 21		NP_570856.2	Q9HBG4A0A024R791

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7 link	c.5T>C	p.Val2Ala	missense_variant	Exon 3 of 22	1	NM_020632.3	ENSP00000308122.2		Q9HBG4

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108749

AN:

151864

Hom.:

39244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.744

Gnomad AMI

AF:

0.773

Gnomad AMR

AF:

0.617

Gnomad ASJ

AF:

0.766

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.770

Gnomad FIN

AF:

0.749

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.724

Gnomad OTH

AF:

0.721

GnomAD2 exomes

AF:

0.693

AC:

174239

AN:

251418

AF XY:

0.703

show subpopulations

Gnomad AFR exome

AF:

0.743

Gnomad AMR exome

AF:

0.532

Gnomad ASJ exome

AF:

0.757

Gnomad EAS exome

AF:

0.483

Gnomad FIN exome

AF:

0.753

Gnomad NFE exome

AF:

0.728

Gnomad OTH exome

AF:

0.715

GnomAD4 exome

AF:

0.718

AC:

1048445

AN:

1460470

Hom.:

378659

Cov.:

AF XY:

0.720

AC XY:

523470

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.749

AC:

25034

AN:

33430

American (AMR)

AF:

0.540

AC:

24151

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.759

AC:

19840

AN:

26130

East Asian (EAS)

AF:

0.513

AC:

20352

AN:

39674

South Asian (SAS)

AF:

0.774

AC:

66722

AN:

86226

European-Finnish (FIN)

AF:

0.752

AC:

40122

AN:

53376

Middle Eastern (MID)

AF:

0.740

AC:

4263

AN:

5762

European-Non Finnish (NFE)

AF:

0.725

AC:

804807

AN:

1110804

Other (OTH)

AF:

0.715

AC:

43154

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

15850

31700

47549

63399

79249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.716

AC:

108840

AN:

151982

Hom.:

39285

Cov.:

AF XY:

0.715

AC XY:

53096

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.745

AC:

30875

AN:

41448

American (AMR)

AF:

0.616

AC:

9403

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

2660

AN:

3472

East Asian (EAS)

AF:

0.513

AC:

2637

AN:

5144

South Asian (SAS)

AF:

0.769

AC:

3697

AN:

4806

European-Finnish (FIN)

AF:

0.749

AC:

7913

AN:

10560

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.724

AC:

49199

AN:

67976

Other (OTH)

AF:

0.722

AC:

1524

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

1578

3156

4734

6312

7890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.719

Hom.:

133337

Bravo

AF:

0.702

TwinsUK

AF:

0.708

AC:

2627

ALSPAC

AF:

0.718

AC:

2768

ESP6500AA

AF:

0.746

AC:

3287

ESP6500EA

AF:

0.725

AC:

6236

ExAC

AF:

0.704

AC:

85464

Asia WGS

AF:

0.652

AC:

2265

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.724

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val2Ala in exon 3 of ATP6V0A4: This variant is not expected to have clinical s ignificance because it has been identified in 77.42% (12784/16512) of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs10258719). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24564331, 27535533) -

Autosomal recessive distal renal tubular acidosis

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bailey-Bloch congenital myopathy

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Val2Ala variant in ATP6V0A4 has been identified in a Turkish individual with sensorineural hearing loss and distal renal tubular acidosis from a consanguineous family (PMID: 24564331). However, this variant is classified as benign for autosomal recessive sensorineural hearing loss and distal renal tubular acidosis because it has been identified in >70% of chromosomes by ExAC (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.057

T;T;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.18

.;T;.;.;T

MetaRNN

Benign

7.5e-7

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.6

N;N;N;N;.

PhyloP100

1.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

2.4

N;N;.;N;.

REVEL

Benign

0.21

Sift

Benign

0.12

T;T;.;T;.

Sift4G

Benign

0.19

T;T;.;T;.

Polyphen

0.0

B;B;B;B;.

Vest4

0.011

MPC

0.23

ClinPred

0.0039

GERP RS

1.9

Varity_R

0.029

gMVP

0.18

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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chr7-138771243-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over