rs200728096
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000053.4(ATP7B):c.1915C>T(p.His639Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000589 in 1,613,938 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 (★★).
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.1915C>T | p.His639Tyr | missense_variant | Exon 6 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249584Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135406
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727200
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74344
ClinVar
Submissions by phenotype
Wilson disease Uncertain:6Other:1
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This missense variant replaces histidine with tyrosine at codon 639 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies suggest that this variant may not impact copper transport (PMID: 24706876). This variant has been reported in an individual affected with Wilson disease (PMID: 16283883). This variant has been identified in 22/280984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 639 of the ATP7B protein (p.His639Tyr). This variant is present in population databases (rs200728096, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease or bipolar disorder (PMID: 16283883, 30556376). ClinVar contains an entry for this variant (Variation ID: 500690). 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 ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 24706876). 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. -
not provided Uncertain:3
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Published functional studies performed on patient fibroblast cells found this variant did not significantly impair copper transport activity (Braiterman LT et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30556376, 18371106, 30032850, 16283883, 29564470, 24706876, 30230192) -
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not specified Uncertain:1
Variant summary: ATP7B c.1915C>T (p.His639Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249584 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (5.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.1915C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual reportedly affected with Wilson Disease (example, Gromadzka_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. At least one publication reports experimental evidence evaluating an impact on protein function (Braiterman_2014). These results showed no damaging effect of this variant on trafficking by demonstrating normal copper transport activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at