rs61747674

Positions:

chr7-138749314-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020632.3(ATP6V0A4):c.1033C>A(p.Leu345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,549,738 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 44 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.42

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01126197).

BP6

Variant 7-138749314-G-T is Benign according to our data. Variant chr7-138749314-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 261340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138749314-G-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP6V0A4	NM_020632.3 linkuse as main transcript	c.1033C>A	p.Leu345Ile	missense_variant	12/22	ENST00000310018.7	NP_065683.2
ATP6V0A4	NM_130840.3 linkuse as main transcript	c.1033C>A	p.Leu345Ile	missense_variant	11/21		NP_570855.2
ATP6V0A4	NM_130841.3 linkuse as main transcript	c.1033C>A	p.Leu345Ile	missense_variant	11/21		NP_570856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7 linkuse as main transcript	c.1033C>A	p.Leu345Ile	missense_variant	12/22	1	NM_020632.3	ENSP00000308122	P1

Frequencies

GnomAD3 genomes

AF:

0.00594

AC:

840

AN:

141480

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00840

Gnomad ASJ

AF:

0.000887

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.000472

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00658

Gnomad NFE

AF:

0.00878

Gnomad OTH

AF:

0.00866

GnomAD3 exomes

AF:

0.00466

AC:

1132

AN:

242760

Hom.:

AF XY:

0.00455

AC XY:

601

AN XY:

132058

show subpopulations

Gnomad AFR exome

AF:

0.00208

Gnomad AMR exome

AF:

0.00604

Gnomad ASJ exome

AF:

0.00122

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00212

Gnomad NFE exome

AF:

0.00696

Gnomad OTH exome

AF:

0.00660

GnomAD4 exome

AF:

0.00769

AC:

10832

AN:

1408138

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

5227

AN XY:

702280

show subpopulations

Gnomad4 AFR exome

AF:

0.00238

Gnomad4 AMR exome

AF:

0.00641

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.00911

Gnomad4 OTH exome

AF:

0.00769

GnomAD4 genome

AF:

0.00593

AC:

840

AN:

141600

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

402

AN XY:

68618

show subpopulations

Gnomad4 AFR

AF:

0.00288

Gnomad4 AMR

AF:

0.00831

Gnomad4 ASJ

AF:

0.000887

Gnomad4 EAS

AF:

0.000202

Gnomad4 SAS

AF:

0.000472

Gnomad4 FIN

AF:

0.00227

Gnomad4 NFE

AF:

0.00880

Gnomad4 OTH

AF:

0.00857

Alfa

AF:

0.00647

Hom.:

Bravo

AF:

0.00534

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00408

AC:

495

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATP6V0A4: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autosomal recessive distal renal tubular acidosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T;.;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.82

.;T;.;D;T;.

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.2

L;L;L;.;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.88

N;N;.;.;.;N

REVEL

Benign

0.28

Sift

Benign

0.11

T;T;.;.;.;T

Sift4G

Benign

0.14

T;T;.;.;.;T

Polyphen

0.87

P;P;P;.;.;P

Vest4

0.24

MVP

0.77

MPC

0.47

ClinPred

0.015

GERP RS

2.7

Varity_R

0.071

gMVP

0.33

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

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