rs373748155
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000053.4(ATP7B):c.3863C>T(p.Thr1288Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,026 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1288R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3863C>T | p.Thr1288Met | missense_variant | 18/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3863C>T | p.Thr1288Met | missense_variant | 18/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249536Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135386
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461820Hom.: 0 Cov.: 35 AF XY: 0.0000289 AC XY: 21AN XY: 727222
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
Wilson disease Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces threonine with methionine at codon 1288 of the ATP7B protein (p.Thr1288Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs373748155, ExAC 0.001%). This missense change has been observed in individual(s) with Wilson disease (PMID: 20967755). ClinVar contains an entry for this variant (Variation ID: 554964). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 13, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 02, 2018 | Variant summary: ATP7B c.3863C>T (p.Thr1288Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246210 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.1e-06 vs 0.0054), allowing no conclusion about variant significance. c.3863C>T has been reported in the literature in at least 2 individuals affected with Wilson Disease (Lepori_2007, Nicastro_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at