7-138733046-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.1739T>C(p.Met580Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,613,950 control chromosomes in the GnomAD database, including 3,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M580I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.091 ( 1002 hom., cov: 31)

Exomes 𝑓: 0.056 ( 2997 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 9.32

Publications

29 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=0.0022696257).

BP6

Variant 7-138733046-A-G is Benign according to our data. Variant chr7-138733046-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP6V0A4	NM_020632.3	MANE Select	c.1739T>C	p.Met580Thr	missense	Exon 17 of 22	NP_065683.2
ATP6V0A4	NM_130840.3		c.1739T>C	p.Met580Thr	missense	Exon 16 of 21	NP_570855.2
ATP6V0A4	NM_130841.3		c.1739T>C	p.Met580Thr	missense	Exon 16 of 21	NP_570856.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP6V0A4	ENST00000310018.7	TSL:1 MANE Select	c.1739T>C	p.Met580Thr	missense	Exon 17 of 22	ENSP00000308122.2
ATP6V0A4	ENST00000353492.4	TSL:1	c.1739T>C	p.Met580Thr	missense	Exon 16 of 21	ENSP00000253856.6
ATP6V0A4	ENST00000393054.5	TSL:5	c.1739T>C	p.Met580Thr	missense	Exon 16 of 21	ENSP00000376774.1

Frequencies

GnomAD3 genomes

AF:

0.0908

AC:

13799

AN:

152026

Hom.:

992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.0985

Gnomad EAS

AF:

0.0560

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0455

Gnomad OTH

AF:

0.0900

GnomAD2 exomes

AF:

0.0658

AC:

16551

AN:

251412

AF XY:

0.0666

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.0376

Gnomad ASJ exome

AF:

0.0939

Gnomad EAS exome

AF:

0.0546

Gnomad FIN exome

AF:

0.0371

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0601

GnomAD4 exome

AF:

0.0559

AC:

81714

AN:

1461806

Hom.:

2997

Cov.:

AF XY:

0.0571

AC XY:

41515

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.192

AC:

6431

AN:

33476

American (AMR)

AF:

0.0397

AC:

1774

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0926

AC:

2419

AN:

26136

East Asian (EAS)

AF:

0.0679

AC:

2694

AN:

39700

South Asian (SAS)

AF:

0.119

AC:

10234

AN:

86258

European-Finnish (FIN)

AF:

0.0366

AC:

1953

AN:

53420

Middle Eastern (MID)

AF:

0.104

AC:

602

AN:

5768

European-Non Finnish (NFE)

AF:

0.0464

AC:

51548

AN:

1111934

Other (OTH)

AF:

0.0672

AC:

4059

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4530

9059

13589

18118

22648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2152

4304

6456

8608

10760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0910

AC:

13851

AN:

152144

Hom.:

1002

Cov.:

AF XY:

0.0908

AC XY:

6756

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.194

AC:

8052

AN:

41456

American (AMR)

AF:

0.0554

AC:

846

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0985

AC:

342

AN:

3472

East Asian (EAS)

AF:

0.0559

AC:

289

AN:

5168

South Asian (SAS)

AF:

0.118

AC:

568

AN:

4818

European-Finnish (FIN)

AF:

0.0365

AC:

387

AN:

10606

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0455

AC:

3096

AN:

68022

Other (OTH)

AF:

0.0942

AC:

199

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

602

1204

1807

2409

3011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0612

Hom.:

1921

Bravo

AF:

0.0959

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0496

AC:

191

ESP6500AA

AF:

0.185

AC:

817

ESP6500EA

AF:

0.0479

AC:

412

ExAC

AF:

0.0691

AC:

8390

Asia WGS

AF:

0.137

AC:

476

AN:

3478

EpiCase

AF:

0.0478

EpiControl

AF:

0.0468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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: 16611712, 27884173, 10973252, 20981092, 24252324)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

not specified

Benign:2

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive distal renal tubular acidosis

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 25, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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

Pathogenic:1

Sep 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

9.3

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.65

Sift

Benign

0.032

Sift4G

Uncertain

0.040

Polyphen

0.77

Vest4

0.26

MPC

0.41

ClinPred

0.051

GERP RS

5.8

Varity_R

0.42

gMVP

0.74

Mutation Taster

=95/5

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over