rs150777839

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020632.3(ATP6V0A4):c.2035G>T(p.Asp679Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,168 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 52 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.222

Publications

12 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=0.0078112483).

BP6

Variant 7-138722001-C-A is Benign according to our data. Variant chr7-138722001-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (788/152300) while in subpopulation NFE AF = 0.0075 (510/68024). AF 95% confidence interval is 0.00696. There are 6 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3 link	c.2035G>T	p.Asp679Tyr	missense_variant	Exon 19 of 22	ENST00000310018.7	NP_065683.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130840.3 link	c.2035G>T	p.Asp679Tyr	missense_variant	Exon 18 of 21		NP_570855.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130841.3 link	c.2035G>T	p.Asp679Tyr	missense_variant	Exon 18 of 21		NP_570856.2	Q9HBG4A0A024R791

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7 link	c.2035G>T	p.Asp679Tyr	missense_variant	Exon 19 of 22	1	NM_020632.3	ENSP00000308122.2		Q9HBG4

Frequencies

GnomAD3 genomes

AF:

0.00517

AC:

787

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00606

AC:

1523

AN:

251434

AF XY:

0.00656

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00599

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00724

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00681

AC:

9962

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

5050

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33480

American (AMR)

AF:

0.00622

AC:

278

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

547

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00693

AC:

598

AN:

86256

European-Finnish (FIN)

AF:

0.00131

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00709

AC:

7880

AN:

1112002

Other (OTH)

AF:

0.00783

AC:

473

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

588

1177

1765

2354

2942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

310

620

930

1240

1550

<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:

0.00517

AC:

788

AN:

152300

Hom.:

Cov.:

AF XY:

0.00500

AC XY:

372

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41574

American (AMR)

AF:

0.00576

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00497

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00750

AC:

510

AN:

68024

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00746

Hom.:

Bravo

AF:

0.00528

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00566

AC:

687

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24252324, 28233610, 16611712, 27884173) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATP6V0A4: BP4, BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP6V0A4 c.2035G>T (p.Asp679Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 251434 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP6V0A4 causing Renal Tubular Acidosis, Distal, Autosomal Recessive phenotype (0.0011), strongly suggesting that the variant is benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive distal renal tubular acidosis

Benign:1

Apr 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

T;T;T;.;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.59

.;T;.;T;T;.

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.0078

T;T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.3

L;L;L;.;.;L

PhyloP100

-0.22

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.2

N;N;.;.;.;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.010

D;D;.;.;.;D

Sift4G

Uncertain

0.026

D;D;.;.;.;D

Polyphen

0.60

P;P;P;.;.;P

Vest4

0.31

MVP

0.75

MPC

0.34

ClinPred

0.016

GERP RS

-2.4

Varity_R

0.071

gMVP

0.42

Mutation Taster

=98/2

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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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