rs143509747

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000330342.8(ATP6V0A2):c.422G>A(p.Arg141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ATP6V0A2
ENST00000330342.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.71

Variant links:

Genes affected

ATP6V0A2 (HGNC:18481): (ATPase H+ transporting V0 subunit a2) The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Mutations in this gene are a cause of both cutis laxa type II and wrinkly skin syndrome. [provided by RefSeq, Jul 2009]

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32170385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP6V0A2	NM_012463.4 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	4/20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	4/19		XP_024304678.1
ATP6V0A2	XM_024448911.2 linkuse as main transcript	c.-3G>A		5_prime_UTR_variant	1/16		XP_024304679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 linkuse as main transcript	c.422G>A	p.Arg141His	missense_variant	4/20	1	NM_012463.4	ENSP00000332247	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251460

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

ALG9 congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the ATP6V0A2 protein (p.Arg141His). This variant is present in population databases (rs143509747, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATP6V0A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1303408). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP6V0A2 protein function. 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. -

Cutis laxa with osteodystrophy;C0406587:Wrinkly skin syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.2

N;.;N

REVEL

Uncertain

0.46

Sift

Benign

0.043

D;.;D

Sift4G

Benign

0.079

T;D;D

Polyphen

0.12

B;D;.

Vest4

0.59

MVP

0.65

MPC

0.76

ClinPred

0.20

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.63

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