12-123712566-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_012463.4(ATP6V0A2):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,433,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

ATP6V0A2
NM_012463.4 start_lost

Scores

5
7
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.29
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 Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_012463.4 (ATP6V0A2) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-123712566-A-T is Pathogenic according to our data. Variant chr12-123712566-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3337835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP6V0A2NM_012463.4 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/20 ENST00000330342.8 NP_036595.2
ATP6V0A2XM_024448910.2 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/19 XP_024304678.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP6V0A2ENST00000330342.8 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/201 NM_012463.4 ENSP00000332247 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000558
AC:
8
AN:
1433742
Hom.:
0
Cov.:
33
AF XY:
0.00000562
AC XY:
4
AN XY:
711668
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000726
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundSep 12, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
25
DANN
Benign
0.95
DEOGEN2
Uncertain
0.59
D;.
Eigen
Benign
-0.079
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
-0.21
T
MutationTaster
Benign
1.0
D
PROVEAN
Uncertain
-2.5
D;.
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0080
D;.
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.95
P;B
Vest4
0.85
MutPred
0.71
Gain of catalytic residue at R6 (P = 0.0457);Gain of catalytic residue at R6 (P = 0.0457);
MVP
0.48
ClinPred
0.98
D
GERP RS
-0.074
Varity_R
0.41
gMVP
0.42

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: rs760441473; hg19: chr12-124197113; API