12-123712566-A-T

Variant names:

• chr12-123712566-A-T
• rs760441473
• NM_012463.4:c.1A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PS1_Moderate PM2 PP5_Moderate

The NM_012463.4(ATP6V0A2):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.29

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]

LOC105370042 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 10 codons. Genomic position: 123712593. Lost 0.011 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
ATP6V0A2	NM_012463.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 20	ENST00000330342.8	NP_036595.2
ATP6V0A2	XM_024448910.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 19		XP_024304678.1
LOC105370042	XR_945477.4	n.*200T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V0A2	ENST00000330342.8	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 20	1	NM_012463.4	ENSP00000332247.2

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

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

Submissions by phenotype

not provided Pathogenic:1

Sep 12, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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

Other links and lift over

dbSNP: rs760441473; hg19: chr12-124197113;