chr3-113778818-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001690.4(ATP6V1A):c.65A>G(p.His22Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000977 in 1,432,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ATP6V1A
NM_001690.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ATP6V1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.3731 (above the threshold of 3.09). Trascript score misZ: 4.7152 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive cutis laxa type 2, classic type, undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 3, autosomal recessive cutis laxa type 2D.

BP4

Computational evidence support a benign effect (MetaRNN=0.24629527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1A	NM_001690.4 link	c.65A>G	p.His22Arg	missense_variant	Exon 2 of 15	ENST00000273398.8	NP_001681.2	P38606-1
ATP6V1A	XM_047448305.1 link	c.65A>G	p.His22Arg	missense_variant	Exon 2 of 15		XP_047304261.1
ATP6V1A	XM_047448306.1 link	c.65A>G	p.His22Arg	missense_variant	Exon 3 of 16		XP_047304262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1A	ENST00000273398.8 link	c.65A>G	p.His22Arg	missense_variant	Exon 2 of 15	1	NM_001690.4	ENSP00000273398.3		P38606-1
ATP6V1A	ENST00000703904.2 link	c.65A>G	p.His22Arg	missense_variant	Exon 3 of 16			ENSP00000515542.1		P38606-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000434

AC:

AN:

230574

Hom.:

AF XY:

0.00000799

AC XY:

AN XY:

125194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000938

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000977

AC:

AN:

1432500

Hom.:

Cov.:

AF XY:

0.00000842

AC XY:

AN XY:

712422

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:

0.0000127

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65A>G (p.H22R) alteration is located in exon 2 (coding exon 1) of the ATP6V1A gene. This alteration results from a A to G substitution at nucleotide position 65, causing the histidine (H) at amino acid position 22 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Dec 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs768359551, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with ATP6V1A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 22 of the ATP6V1A protein (p.His22Arg). -

Developmental and epileptic encephalopathy 93

Uncertain:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are suggested mechanisms of disease in this gene and are associated with dominant developmental and epileptic encephalopathy 93 (MIM#618012) (PMID: 29668857). Loss of function is also a suggested mechanism associated with recessive cutis laxa type IID (MIM#617403) (PMID: 28065471). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ATP synthase alpha/beta family, beta-barrel domain (Decipher). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.073

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.64

N;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;D

REVEL

Uncertain

0.34

Sift

Benign

0.29

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.49

MutPred

0.38

Gain of phosphorylation at S25 (P = 0.0749);Gain of phosphorylation at S25 (P = 0.0749);

MVP

0.83

MPC

0.89

ClinPred

0.54

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over