chr17-42494445-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_001130021.3(ATP6V0A1):c.1286G>A(p.Arg429Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,612,996 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: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
ATP6V0A1
NM_001130021.3 missense
NM_001130021.3 missense
Scores
2
7
9
Clinical Significance
Conservation
PhyloP100: 9.99
Genes affected
ATP6V0A1 (HGNC:865): (ATPase H+ transporting V0 subunit a1) 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 gene encodes one of three A subunit proteins and the encoded protein is associated with clathrin-coated vesicles. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ATP6V0A1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21465352).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00024 (350/1461014) while in subpopulation NFE AF= 0.000297 (330/1111612). AF 95% confidence interval is 0.00027. There are 0 homozygotes in gnomad4_exome. There are 158 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V0A1 | NM_001130021.3 | c.1286G>A | p.Arg429Gln | missense_variant | 12/22 | ENST00000343619.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V0A1 | ENST00000343619.9 | c.1286G>A | p.Arg429Gln | missense_variant | 12/22 | 1 | NM_001130021.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000178 AC: 27AN: 151982Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000136 AC: 34AN: 250562Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135362
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GnomAD4 exome AF: 0.000240 AC: 350AN: 1461014Hom.: 0 Cov.: 30 AF XY: 0.000217 AC XY: 158AN XY: 726778
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GnomAD4 genome ? AF: 0.000178 AC: 27AN: 151982Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74204
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2021 | The c.1307G>A (p.R436Q) alteration is located in exon 12 (coding exon 11) of the ATP6V0A1 gene. This alteration results from a G to A substitution at nucleotide position 1307, causing the arginine (R) at amino acid position 436 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;L;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;.;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
B;B;.;B;D;.
Vest4
MVP
MPC
2.1
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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