NM_001690.4:c.-13-81A>G

Variant names:

• chr3-113778660-A-G
• rs12636577
• NM_001690.4:c.-13-81A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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]

ATP6V1A Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 93

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive cutis laxa type 2D

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001690.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1A	NM_001690.4	MANE Select	c.-13-81A>G		intron	N/A	NP_001681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6V1A	ENST00000273398.8	TSL:1 MANE Select	c.-13-81A>G		intron	N/A	ENSP00000273398.3	P38606-1
	ATP6V1A	ENST00000703904.2		c.-13-81A>G		intron	N/A	ENSP00000515542.1	P38606-1
	ATP6V1A	ENST00000703910.1		c.-13-81A>G		intron	N/A	ENSP00000515547.1	P38606-1

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

African (AFR) AF: 0.309 AC: 3406 AN: 11010

American (AMR) AF: 0.228 AC: 2738 AN: 12032

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 3119 AN: 12570

East Asian (EAS) AF: 0.406 AC: 10583 AN: 26054

South Asian (SAS) AF: 0.212 AC: 5949 AN: 28114

European-Finnish (FIN) AF: 0.462 AC: 18549 AN: 40176

Middle Eastern (MID) AF: 0.285 AC: 538 AN: 1890

European-Non Finnish (NFE) AF: 0.353 AC: 121711 AN: 344932

Other (OTH) AF: 0.323 AC: 8382 AN: 25964

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

African (AFR) AF: 0.305 AC: 12658 AN: 41470

American (AMR) AF: 0.250 AC: 3813 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1882 AN: 5174

South Asian (SAS) AF: 0.214 AC: 1030 AN: 4822

European-Finnish (FIN) AF: 0.452 AC: 4760 AN: 10538

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24333 AN: 67962

Other (OTH) AF: 0.306 AC: 647 AN: 2112

Alfa AF: 0.345 Hom.: 1191

Bravo AF: 0.317

Asia WGS AF: 0.252 AC: 872 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.8
DANN	Benign	0.91
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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