rs746407800

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001690.4(ATP6V1A):c.31G>A(p.Asp11Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000069 in 1,593,718 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D11H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ATP6V1A
NM_001690.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.34

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy 93
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive cutis laxa type 2D
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Genomics England PanelApp, Ambry Genetics
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

ATP6V1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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 2D, developmental and epileptic encephalopathy 93, autosomal recessive cutis laxa type 2, classic type, undetermined early-onset epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.2307382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1A	NM_001690.4 link	c.31G>A	p.Asp11Asn	missense_variant	Exon 2 of 15	ENST00000273398.8	NP_001681.2	P38606-1
ATP6V1A	XM_047448305.1 link	c.31G>A	p.Asp11Asn	missense_variant	Exon 2 of 15		XP_047304261.1
ATP6V1A	XM_047448306.1 link	c.31G>A	p.Asp11Asn	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.31G>A	p.Asp11Asn	missense_variant	Exon 2 of 15	1	NM_001690.4	ENSP00000273398.3		P38606-1
ATP6V1A	ENST00000703904.2 link	c.31G>A	p.Asp11Asn	missense_variant	Exon 3 of 16			ENSP00000515542.1		P38606-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000250

AC:

AN:

240208

AF XY:

0.0000307

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000293

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000624

AC:

AN:

1441684

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

716984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32676

American (AMR)

AF:

0.00

AC:

AN:

42494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25658

East Asian (EAS)

AF:

0.000156

AC:

AN:

38418

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102486

Other (OTH)

AF:

0.0000169

AC:

AN:

59332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 11 of the ATP6V1A protein (p.Asp11Asn). This variant is present in population databases (rs746407800, gnomAD 0.03%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 25363768). ClinVar contains an entry for this variant (Variation ID: 2139656). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.4

L;.

PhyloP100

6.3

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.069

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.016

B;.

Vest4

0.28

MutPred

0.20

Gain of methylation at K8 (P = 0.0719);Gain of methylation at K8 (P = 0.0719);

MVP

0.80

MPC

0.72

ClinPred

0.21

GERP RS

5.4

Varity_R

0.096

gMVP

0.70

Mutation Taster

=232/68

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs746407800

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over