rs781838938
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001692.4(ATP6V1B1):āc.1037C>Gā(p.Pro346Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Consequence
NM_001692.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP6V1B1 | NM_001692.4 | c.1037C>G | p.Pro346Arg | missense_variant | 10/14 | ENST00000234396.10 | NP_001683.2 | |
ATP6V1B1 | XM_011532907.3 | c.1157C>G | p.Pro386Arg | missense_variant | 9/13 | XP_011531209.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP6V1B1 | ENST00000234396.10 | c.1037C>G | p.Pro346Arg | missense_variant | 10/14 | 1 | NM_001692.4 | ENSP00000234396.4 | ||
ENSG00000258881 | ENST00000606025.5 | c.476-20856G>C | intron_variant | 5 | ENSP00000475641.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250624Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135596
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461132Hom.: 0 Cov.: 36 AF XY: 0.0000179 AC XY: 13AN XY: 726910
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Renal tubular acidosis with progressive nerve deafness Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 27, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2023 | Published functional studies demonstrate a damaging effect; specifically, rat inner medullary collecting duct cells transfected with the P346R variant showed significantly reduced pHi recovery after an acute acid load compared to wild type, and functional analysis found that P346R is associated with non-measurable ATPase activity (Yang et al., 2006); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9916796, 18368028, 25498251, 27247958, 34805638, 33226606, 25741868, 31959358, 31618753, 16611712, 28188436, 22509993, 16769747) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2023 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 346 of the ATP6V1B1 protein (p.Pro346Arg). This variant is present in population databases (rs781838938, gnomAD 0.006%). This missense change has been observed in individuals with renal tubular acidosis (PMID: 16611712, 22509993, 27247958, 28188436). ClinVar contains an entry for this variant (Variation ID: 280139). 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 expected to disrupt ATP6V1B1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP6V1B1 function (PMID: 16769747, 18368028). For these reasons, this variant has been classified as Pathogenic. - |
Distal renal tubular acidosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 22, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at