7-138706632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020632.3(ATP6V0A4):c.2515G>A(p.Glu839Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.00

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP6V0A4	NM_020632.3 linkuse as main transcript	c.2515G>A	p.Glu839Lys	missense_variant	22/22	ENST00000310018.7
ATP6V0A4	NM_130840.3 linkuse as main transcript	c.2515G>A	p.Glu839Lys	missense_variant	21/21
ATP6V0A4	NM_130841.3 linkuse as main transcript	c.2515G>A	p.Glu839Lys	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7 linkuse as main transcript	c.2515G>A	p.Glu839Lys	missense_variant	22/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251254

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.2515G>A (p.E839K) alteration is located in exon 22 (coding exon 20) of the ATP6V0A4 gene. This alteration results from a G to A substitution at nucleotide position 2515, causing the glutamic acid (E) at amino acid position 839 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 839 of the ATP6V0A4 protein (p.Glu839Lys). This variant is present in population databases (rs374305455, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATP6V0A4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.090

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.18

T;T;T;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.51

D;D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.5

M;M;M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

N;N;.;.;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;D;.;.;D

Sift4G

Uncertain

0.021

D;D;.;.;D

Polyphen

0.98

D;D;D;.;D

Vest4

0.32

MVP

0.90

MPC

0.48

ClinPred

0.84

GERP RS

4.9

Varity_R

0.16

gMVP

0.36

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