rs1555282191
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000053.4(ATP7B):โc.4283_4284insTโ(p.Ser1429ValfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (โ โ ). Synonymous variant affecting the same amino acid position (i.e. V1428V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes ๐: 0.0000014 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 frameshift
NM_000053.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.95
Genes affected
ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-51934870-C-CA is Pathogenic according to our data. Variant chr13-51934870-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.4283_4284insT | p.Ser1429ValfsTer20 | frameshift_variant | 21/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.4283_4284insT | p.Ser1429ValfsTer20 | frameshift_variant | 21/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461860Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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30
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727236
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Mar 23, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATP7B protein in which other variant(s) (p.Arg1459Glyfs*2) have been determined to be pathogenic (PMID: 26799313). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 551073). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1429Valfs*20) in the ATP7B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the ATP7B protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This variant inserts 1 nucleotide in exon 21 of the ATP7B gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein with the last 37 amino acids at the C-terminus disrupted. In addition, a truncating variant occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 1071568). To our knowledge, this variant has not been reported in individuals affected with Wilson disease in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although the mechanism by which this variant causes disease is not clearly understood, the available clinical evidence indicates that this variant is associated with disease. Therefore, this variant is classified as Likely Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at