rs3807154

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020632.3(ATP6V0A4):c.1812T>C(p.His604His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,270 control chromosomes in the GnomAD database, including 410,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34209 hom., cov: 30)

Exomes 𝑓: 0.72 ( 376173 hom. )

Consequence

ATP6V0A4
NM_020632.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0700

Publications

33 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 7-138732973-A-G is Benign according to our data. Variant chr7-138732973-A-G is described in ClinVar as Benign. ClinVar VariationId is 261343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ATP6V0A4	NM_020632.3 link	c.1812T>C	p.His604His	synonymous_variant	Exon 17 of 22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3 link	c.1812T>C	p.His604His	synonymous_variant	Exon 16 of 21		NP_570855.2
ATP6V0A4	NM_130841.3 link	c.1812T>C	p.His604His	synonymous_variant	Exon 16 of 21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7 link	c.1812T>C	p.His604His	synonymous_variant	Exon 17 of 22	1	NM_020632.3	ENSP00000308122.2

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100206

AN:

151724

Hom.:

34202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.799

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.690

Gnomad EAS

AF:

0.812

Gnomad SAS

AF:

0.738

Gnomad FIN

AF:

0.768

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.717

Gnomad OTH

AF:

0.655

GnomAD2 exomes

AF:

0.729

AC:

183187

AN:

251388

AF XY:

0.730

show subpopulations

Gnomad AFR exome

AF:

0.457

Gnomad AMR exome

AF:

0.830

Gnomad ASJ exome

AF:

0.696

Gnomad EAS exome

AF:

0.822

Gnomad FIN exome

AF:

0.763

Gnomad NFE exome

AF:

0.716

Gnomad OTH exome

AF:

0.730

GnomAD4 exome

AF:

0.715

AC:

1045437

AN:

1461428

Hom.:

376173

Cov.:

AF XY:

0.717

AC XY:

521051

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.465

AC:

15564

AN:

33466

American (AMR)

AF:

0.822

AC:

36758

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.691

AC:

18064

AN:

26134

East Asian (EAS)

AF:

0.795

AC:

31571

AN:

39698

South Asian (SAS)

AF:

0.734

AC:

63296

AN:

86256

European-Finnish (FIN)

AF:

0.763

AC:

40737

AN:

53420

Middle Eastern (MID)

AF:

0.702

AC:

4049

AN:

5768

European-Non Finnish (NFE)

AF:

0.713

AC:

792602

AN:

1111592

Other (OTH)

AF:

0.709

AC:

42796

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

16813

33626

50438

67251

84064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19806

39612

59418

79224

99030

<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:

0.660

AC:

100240

AN:

151842

Hom.:

34209

Cov.:

AF XY:

0.665

AC XY:

49374

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.470

AC:

19453

AN:

41370

American (AMR)

AF:

0.759

AC:

11566

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

2396

AN:

3470

East Asian (EAS)

AF:

0.812

AC:

4193

AN:

5166

South Asian (SAS)

AF:

0.739

AC:

3544

AN:

4798

European-Finnish (FIN)

AF:

0.768

AC:

8098

AN:

10550

Middle Eastern (MID)

AF:

0.714

AC:

210

AN:

294

European-Non Finnish (NFE)

AF:

0.717

AC:

48683

AN:

67940

Other (OTH)

AF:

0.651

AC:

1370

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1655

3310

4966

6621

8276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.698

Hom.:

68966

Bravo

AF:

0.653

Asia WGS

AF:

0.731

AC:

2541

AN:

3478

EpiCase

AF:

0.719

EpiControl

AF:

0.727

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.093

(source)

DANN

Benign

0.36

PhyloP100

-0.070

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over