rs753962912
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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):c.1745_1746delTA(p.Ile582fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 frameshift
NM_000053.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.89
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 13-51964994-CTA-C is Pathogenic according to our data. Variant chr13-51964994-CTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.1745_1746delTA | p.Ile582fs | frameshift_variant | 5/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249568Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135394
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461890Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727248
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GnomAD4 genome 0.0000394 AC: 6AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74424
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 05, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change creates a premature translational stop signal (p.Ile582Argfs*25) 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). This variant is present in population databases (rs753962912, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 17317524, 17949296, 23518715, 27398169). ClinVar contains an entry for this variant (Variation ID: 189112). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | ATP7B NM_000053.3 exon 5 p.Ile582Argfs*25 (1745_1746del): This variant has been reported in the literature in multiple individuals with Wilson disease (Thomas 1995 PMID:7626145, Chappuis 2007 PMID:17317524, Lepori 2007 PMID:17949296, Coffey 2013 PMID:23518715, Hua 2016 PMID:27398169). This variant is also present in 0.004% (6/128706) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-52539130-CTA-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with multiple labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:189112). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 25 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Buiakova 1999 PMID:10441329). In summary, this variant is classified as pathogenic based on the data above. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 16, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 26, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2024 | This variant deletes 2 nucleotides in exon 5 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 reported in individuals affected with Wilson disease (PMID: 17317524, 23518715, 27398169, 34240825, 34400371, 34470610; DOI:10.1134/S1022795419120020). In a family described by Coffey et al, 2013, this variant was found in the compound heterozygous state in a father affected with Wilson disease and an unaffected mother who carried a different variant (p.Val1234Phe). The p.Ile582Argfs*25 variant was identified in the compound heterozygous state in one of their daughters who was affected with Wilson disease and in the heterozygous state in their other daughter who was not affected. This variant has been identified in 6/280960 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Ile582ArgfsX25 variant in ATP7B has been reported in at least 4 individuals with Wilson disease who were compound heterozygous for a second pathogenic variant (Coffey 2013, Hua 2016, Lepori 2007, Loudianos 1999, Thomas 1995). It has been identified in 0.005% (7/128706) 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 582 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2, PP4. - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 31, 2014 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 04, 2020 | PVS1, PS4_moderate, PM2, PP4 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2017 | The c.1745_1746delTA pathogenic mutation, located in coding exon 5 of the ATP7B gene, results from a deletion of two nucleotides at nucleotide positions 1745 to 1746, causing a translational frameshift with a predicted alternate stop codon (p.I582Rfs*25). This mutation has been detected in multiple individuals with Wilson disease (Chappuis P et al. J Trace Elem Med Biol, 2007 Jan;21:37-42; Coffey AJ et al. Brain, 2013 May;136:1476-87; Hua R et al. Am J Transl Res, 2016 Jun;8:2851-61). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Spastic ataxia Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jul 12, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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