rs587776616
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3_ModeratePP5
The NM_020632.3(ATP6V0A4):c.105del(p.Gln36SerfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ATP6V0A4
NM_020632.3 frameshift
NM_020632.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.250
Genes affected
ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent 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. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 7-138771142-GA-G is Pathogenic according to our data. Variant chr7-138771142-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 5153.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-138771142-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V0A4 | NM_020632.3 | c.105del | p.Gln36SerfsTer5 | frameshift_variant | 3/22 | ENST00000310018.7 | |
ATP6V0A4 | NM_130840.3 | c.105del | p.Gln36SerfsTer5 | frameshift_variant | 2/21 | ||
ATP6V0A4 | NM_130841.3 | c.105del | p.Gln36SerfsTer5 | frameshift_variant | 2/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V0A4 | ENST00000310018.7 | c.105del | p.Gln36SerfsTer5 | frameshift_variant | 3/22 | 1 | NM_020632.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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?
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251406Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461776Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727200
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2000 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at