rs776848753
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.4088C>T(p.Ser1363Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S1363C) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.4088C>T | p.Ser1363Phe | missense_variant | 20/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.4088C>T | p.Ser1363Phe | missense_variant | 20/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19937698). 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. ClinVar contains an entry for this variant (Variation ID: 188908). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 21610751, 24094725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1363 of the ATP7B protein (p.Ser1363Phe). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2021 | Variant summary: ATP7B c.4088C>T (p.Ser1363Phe) 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 was absent in 246976 control chromosomes (gnomAD). c.4088C>T (p.Ser1363Phe) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Loudianos_1999, Moller_2011, Mukherjee_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (e.g. van den Berghe_2009). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 23, 2022 | PP3, PP4, PM2, PM3_strong, PS4_moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at