rs1057516893
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):βc.1716delβ(p.Met573Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 frameshift
NM_000053.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.222
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-51965024-TC-T is Pathogenic according to our data. Variant chr13-51965024-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370955.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.1716del | p.Met573Ter | frameshift_variant | 5/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.1716del | p.Met573Ter | frameshift_variant | 5/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727232
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GnomAD4 genome ? Cov.: 32
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2022 | ClinVar contains an entry for this variant (Variation ID: 370955). This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 23551039). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met573*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed frameshift c.1716del (p.Met573Ter) variant in ATP7B gene has been reported previously in individuals affected with Wilson Disease (Aggarwal et al., 2013). Experimental evidences showed this variant reduces the functional activity of ATP7B (Chandhok et al., 2016). The p.Met573Ter variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This sequence change creates a premature translational stop signal (p.Met573Ter) in the ATP7B gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in ATP7B gene have been previously reported to be pathogenic (Chandhok et al., 2016). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 05, 2018 | Variant summary: ATP7B c.1716delG (p.Met573X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Ile582fsX25 and p.Tyr670fsX1). The variant was absent in 246180 control chromosomes in gnomAD. The c.1716delG variant has been reported in the literature in two individuals affected with Wilson Disease, both of whom were described as early-onset of symptoms and a higher burden of disease (Aggarwal_2013). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating several different aspects of protein function; the most pronounced variant effect results in <10% of normal activity (Chandhok_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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