rs771603301
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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):c.4092_4093delGT(p.Ser1365fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 frameshift
NM_000053.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.81
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 50 bp of the penultimate 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 13-51935623-GAC-G is Pathogenic according to our data. Variant chr13-51935623-GAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51935623-GAC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.4092_4093delGT | p.Ser1365fs | frameshift_variant | 20/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.4092_4093delGT | p.Ser1365fs | frameshift_variant | 20/21 | 1 | NM_000053.4 | ENSP00000242839.5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247014Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134362
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GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461456Hom.: 0 AF XY: 0.0000825 AC XY: 60AN XY: 727000
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74394
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:10Other:1
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 06, 2024 | This variant deletes 2 nucleotides in exon 20 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed with co-occurring pathogenic mutations in individuals affected with autosomal recessive Wilson disease (PMID: 15967699, 17317524, 20042865, 23518715, 34400371), indicating that this variant contributes to disease. This variant has been identified in 5/247014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Sep 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 17, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Ser1365CysfsX12 variant in ATP7B has been previously reported in 8 probands with Wilson disease, 5 of whom were compound heterozygous for a second ATP7B variant (Coffey 2013, Lowette 2010, Shah 1994, Thomas 1995, Vrabelova 2005). This variant has also been identified 0.003% (4/111880) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1365 and leads to a premature termination codon 12 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, several pathogenic and likely pathogenic variants have been reported 3' to this variant in ClinVar (Variation IDs 371170, 553449, 280040, 551073). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM2, PM3_Strong, PM4, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Ser1365Cysfs*12) in the ATP7B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the ATP7B protein. This variant is present in population databases (rs771603301, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 17317524, 20042865). ClinVar contains an entry for this variant (Variation ID: 371438). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the ATP7B protein in which other variant(s) (p.Gln1399Argfs*6) have been determined to be pathogenic (PMID: 11054498, 14748773, 28600779). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2017 | Variant summary: The ATP7B c.4092_4093delGT (p.Ser1365Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool, Mutation Taster, predicts a damaging outcome for this variant. This variant is absent in the large control population database ExAC (0/108958 control chromosomes). One clinical diagnostic laboratories and multiple reputable databases classified this variant as pathogenic. In addition, the variant has been reported in numerous patients in the literature. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ATP7B: PM3:Very Strong, PM2, PVS1:Moderate, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2022 | Frameshift variant predicted to result in protein truncation, as the last 101 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18371106, 7626145, 9311736, 30556376, 28600779, 20042865, 14748773, 11054498, 15967699, 17317524, 23518715) - |
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