rs371863168
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001692.4(ATP6V1B1):c.1382C>T(p.Pro461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,930 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. P461T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001692.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP6V1B1 | NM_001692.4 | c.1382C>T | p.Pro461Leu | missense_variant | 14/14 | ENST00000234396.10 | |
ATP6V1B1 | XM_011532907.3 | c.1502C>T | p.Pro501Leu | missense_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP6V1B1 | ENST00000234396.10 | c.1382C>T | p.Pro461Leu | missense_variant | 14/14 | 1 | NM_001692.4 | P1 | |
ATP6V1B1 | ENST00000412314.5 | c.1331C>T | p.Pro444Leu | missense_variant | 14/14 | 5 | |||
ATP6V1B1 | ENST00000433895.2 | c.314C>T | p.Pro105Leu | missense_variant | 5/5 | 3 | |||
VAX2 | ENST00000432367.6 | c.*1158C>T | 3_prime_UTR_variant, NMD_transcript_variant | 15/15 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152236Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251168Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135840
GnomAD4 exome AF: 0.000163 AC: 238AN: 1461694Hom.: 0 Cov.: 33 AF XY: 0.000166 AC XY: 121AN XY: 727140
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152236Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11AN XY: 74380
ClinVar
Submissions by phenotype
Renal tubular acidosis with progressive nerve deafness Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 05, 2015 | The p.Pro461Leu variant in ATP6V1B1 has not been previously reported in individu als with hearing loss. This variant has been identified in 16/66302 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs371863168). Computational prediction tools and conservation anal yses suggest that the p.Pro461Leu variant may not impact the protein, though thi s information is not predictive enough to rule out pathogenicity. In summary, th e clinical significance of the p.Pro461Leu variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2014 | The c.1382C>T (p.P461L) alteration is located in exon 14 (coding exon 14) of the ATP6V1B1 gene. This alteration results from a C to T substitution at nucleotide position 1382, causing the proline (P) at amino acid position 461 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 461 of the ATP6V1B1 protein (p.Pro461Leu). This variant is present in population databases (rs371863168, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATP6V1B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228445). 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 ATP6V1B1 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at