rs143142641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012463.4(ATP6V0A2):c.1486G>A(p.Ala496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000747 in 1,614,146 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 13 hom. )

Consequence

ATP6V0A2
NM_012463.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -0.148

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

wrinkly skin syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
autosomal recessive cutis laxa type 2, classic type
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
autosomal recessive cutis laxa type 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ATP6V0A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013159156).

BP6

Variant 12-123744756-G-A is Benign according to our data. Variant chr12-123744756-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166708.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000512 (78/152254) while in subpopulation SAS AF = 0.00622 (30/4820). AF 95% confidence interval is 0.00448. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4 link	c.1486G>A	p.Ala496Thr	missense_variant	Exon 12 of 20	ENST00000330342.8	NP_036595.2	Q9Y487
ATP6V0A2	XM_024448910.2 link	c.1486G>A	p.Ala496Thr	missense_variant	Exon 12 of 19		XP_024304678.1
ATP6V0A2	XM_024448911.2 link	c.973G>A	p.Ala325Thr	missense_variant	Exon 8 of 16		XP_024304679.1
ATP6V0A2	XM_024448912.2 link	c.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 13		XP_024304680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8 link	c.1486G>A	p.Ala496Thr	missense_variant	Exon 12 of 20	1	NM_012463.4	ENSP00000332247.2		Q9Y487

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00118

AC:

296

AN:

251486

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000650

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000771

AC:

1127

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000986

AC XY:

717

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00664

AC:

573

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000392

AC:

436

AN:

1112012

Other (OTH)

AF:

0.000712

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000512

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41544

American (AMR)

AF:

0.000392

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68004

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000646

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Mar 10, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 24, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATP6V0A2: BP4, BS2 -

not specified

Benign:1

Nov 16, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 08, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATP6V0A2-related disorder

Benign:1

Sep 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

ALG9 congenital disorder of glycosylation

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cutis laxa with osteodystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.60

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.15

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.44

M_CAP

Benign

0.041

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

PhyloP100

-0.15

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.14

REVEL

Benign

0.079

Sift

Benign

0.52

Sift4G

Benign

0.57

Polyphen

0.0020

Vest4

0.069

MVP

0.23

MPC

0.16

ClinPred

0.0050

GERP RS

-4.2

Varity_R

0.017

gMVP

0.45

Mutation Taster

=95/5

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