rs753594031
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000053.4(ATP7B):c.3104G>T(p.Gly1035Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,840 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1035D) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3104G>T | p.Gly1035Val | missense_variant | 14/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3104G>T | p.Gly1035Val | missense_variant | 14/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248810Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135218
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727214
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the ATP7B protein (p.Gly1035Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 9311736, 10070620, 17587212, 21707886, 22940187). ClinVar contains an entry for this variant (Variation ID: 371021). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2022 | Variant summary: ATP7B c.3104G>T (p.Gly1035Val) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of 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 4e-06 in 248810 control chromosomes. c.3104G>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Wilson Disease (example, Tatsumi_2011, Katano_2014, Kyeong Kim_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at