chr3-113781071-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001690.4(ATP6V1A):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,450,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000083 ( 0 hom. )
Consequence
ATP6V1A
NM_001690.4 missense
NM_001690.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 7.36
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP6V1A | NM_001690.4 | c.104C>T | p.Ala35Val | missense_variant | Exon 3 of 15 | ENST00000273398.8 | NP_001681.2 | |
ATP6V1A | XM_047448305.1 | c.104C>T | p.Ala35Val | missense_variant | Exon 3 of 15 | XP_047304261.1 | ||
ATP6V1A | XM_047448306.1 | c.104C>T | p.Ala35Val | missense_variant | Exon 4 of 16 | XP_047304262.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP6V1A | ENST00000273398.8 | c.104C>T | p.Ala35Val | missense_variant | Exon 3 of 15 | 1 | NM_001690.4 | ENSP00000273398.3 | ||
ATP6V1A | ENST00000703904.2 | c.104C>T | p.Ala35Val | missense_variant | Exon 4 of 16 | ENSP00000515542.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000417 AC: 1AN: 239936Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129850
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GnomAD4 exome AF: 0.00000827 AC: 12AN: 1450530Hom.: 0 Cov.: 30 AF XY: 0.00000693 AC XY: 5AN XY: 721328
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GnomAD4 genome Cov.: 32
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32
Bravo
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ESP6500AA
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ESP6500EA
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 29, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the ATP6V1A protein (p.Ala35Val). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP6V1A protein function. This variant has not been reported in the literature in individuals affected with ATP6V1A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at