rs769484789
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The ENST00000242839.10(ATP7B):c.3784G>T(p.Val1262Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1262V) has been classified as Likely benign.
Frequency
Consequence
ENST00000242839.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3784G>T | p.Val1262Phe | missense_variant | 18/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3784G>T | p.Val1262Phe | missense_variant | 18/21 | 1 | NM_000053.4 | ENSP00000242839 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249584Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135410
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461892Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74396
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This variant was detected in multiple affected individuals as homozygous or as compound heterozygous (in trans) with a pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 10544227, 20485189, 20958917, 29930488, 35388883). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 19937698, 35388883). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The p.Val1262Phe variant in ATP7B has been reported in at least 4 individuals with Wilson disease and segregated with disease in 1 affected individual from 1 family (Loudianos 1999 PMID: 10544227, Shim 2018 PMID: 29930488, Song 2022 PMID: 35388883). It has also been identified in 0.001% (1/68052) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 550902). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant reduces ATP7B protein expression (van den Berghe 2009 PMID: 19937698); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP1, PP3, PS3_Supporting. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 18, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1262 of the ATP7B protein (p.Val1262Phe). This variant is present in population databases (rs769484789, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson's disease (PMID: 10544227, 20485189; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550902). 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 ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19937698). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at