rs143142641

Variant summary

Our verdict is Benign. Variant got -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. 16/21 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

19

Clinical Significance

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

Conservation

PhyloP100: -0.148
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 166708.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr12-123744756-G-A is described in Lovd as [Likely_benign].
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP6V0A2NM_012463.4 linkc.1486G>A p.Ala496Thr missense_variant Exon 12 of 20 ENST00000330342.8 NP_036595.2 Q9Y487
ATP6V0A2XM_024448910.2 linkc.1486G>A p.Ala496Thr missense_variant Exon 12 of 19 XP_024304678.1
ATP6V0A2XM_024448911.2 linkc.973G>A p.Ala325Thr missense_variant Exon 8 of 16 XP_024304679.1
ATP6V0A2XM_024448912.2 linkc.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
ATP6V0A2ENST00000330342.8 linkc.1486G>A p.Ala496Thr missense_variant Exon 12 of 20 1 NM_012463.4 ENSP00000332247.2 Q9Y487

Frequencies

GnomAD3 genomes
AF:
0.000519
AC:
79
AN:
152136
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.00118
AC:
296
AN:
251486
Hom.:
4
AF XY:
0.00145
AC XY:
197
AN XY:
135916
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 SAS exome
AF:
0.00581
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.:
13
Cov.:
33
AF XY:
0.000986
AC XY:
717
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00142
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00664
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000392
Gnomad4 OTH exome
AF:
0.000712
GnomAD4 genome
AF:
0.000512
AC:
78
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.000685
AC XY:
51
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000485
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000551
Hom.:
0
Bravo
AF:
0.000287
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.00133
AC:
162
Asia WGS
AF:
0.00202
AC:
7
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

- -

-
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 -

-
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

- -

Sep 24, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
0.60
DANN
Benign
0.71
DEOGEN2
Benign
0.15
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-0.14
N
REVEL
Benign
0.079
Sift
Benign
0.52
T
Sift4G
Benign
0.57
T
Polyphen
0.0020
B
Vest4
0.069
MVP
0.23
MPC
0.16
ClinPred
0.0050
T
GERP RS
-4.2
Varity_R
0.017
gMVP
0.45

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.

Other links and lift over

dbSNP: rs143142641; hg19: chr12-124229303; API