rs12636577

Positions:

• chr3-113778660-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001690.4(ATP6V1A):​c.-13-81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 654,768 control chromosomes in the GnomAD database, including 40,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8529 hom., cov: 32)
  • Exomes 𝑓: 0.35 (31652 hom.)
• Consequence: ATP6V1A NM_001690.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.267

Genes affected

ATP6V1A (HGNC:851): (ATPase H+ transporting V1 subunit A) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This encoded protein is one of two V1 domain A subunit isoforms and is found in all tissues. Transcript variants derived from alternative polyadenylation exist. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-113778660-A-G is Benign according to our data. Variant chr3-113778660-A-G is described in ClinVar as [Benign]. Clinvar id is 1268535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V1A	NM_001690.4	c.-13-81A>G		intron_variant		ENST00000273398.8	NP_001681.2
ATP6V1A	XM_047448305.1	c.-13-81A>G		intron_variant			XP_047304261.1
ATP6V1A	XM_047448306.1	c.-13-81A>G		intron_variant			XP_047304262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V1A	ENST00000273398.8	c.-13-81A>G		intron_variant		1	NM_001690.4	ENSP00000273398	P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50476 AN: 151908 Hom.: 8532 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.311

GnomAD4 exome AF: 0.348 AC: 174975 AN: 502742 Hom.: 31652 AF XY: 0.344 AC XY: 90344 AN XY: 262424

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.323

GnomAD4 genome AF: 0.332 AC: 50476 AN: 152026 Hom.: 8529 Cov.: 32 AF XY: 0.332 AC XY: 24694 AN XY: 74298

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.364

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.306

Alfa AF: 0.346 Hom.: 1146

Bravo AF: 0.317

Asia WGS AF: 0.252 AC: 872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.8
DANN	Benign	0.91

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: rs12636577; hg19: chr3-113497507; COSMIC: COSV56361794;