rs753250853
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.3263T>A(p.Leu1088Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000053.4 stop_gained
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3263T>A | p.Leu1088Ter | stop_gained | 15/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3263T>A | p.Leu1088Ter | stop_gained | 15/21 | 1 | NM_000053.4 | ENSP00000242839 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249552Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135392
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727232
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:10
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 25, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 16, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2021 | Variant summary: ATP7B c.3263T>A (p.Leu1088X) 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. The variant allele was found at a frequency of 8e-06 in 249552 control chromosomes. c.3263T>A has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Deguti_2004, Vrabelova_2005, Merle_2010, Sanchez-Monteagudo_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 20, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188886). This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 12515040, 15024742, 20082719, 23518715). This variant is present in population databases (rs753250853, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Leu1088*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 30, 2018 | The ATP7B c.3263T>A; p.Leu1088Ter variant (rs753250853) has been described in several individuals with Wilson disease (Coffey 2013, Deguti 2004, Merle 2010, Vrabelova 2005). It contains an entry in ClinVar (Variation ID: 188886) and observed on only 2 alleles in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Merle U et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 2010 Jan 18;10:8. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Leu1088X variant in ATP7B has been reported in several individuals with Wilson disease, including at least 2 compound heterozygous individuals (Coffey 2013, Deguti 2004, Merle 2010, Vrabelova 2005). This variant was identified in 0.001% (2/113284) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1088, which is 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, PM2, PM3, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This variant changes 1 nucleotide in exon 15 of the ATP7B gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least ten individuals affected with Wilson disease (PMID: 15024742, 15967699, 20082719, 20958917, 23518715, 29358271, 32043565, 34620762). Among these individuals, this variant was found in the homozygous state (PMID: 29358271) and compound heterozygous state (PMID: 15024742, 23518715, 32043565). This variant has been identified in 2/249552 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 20, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32043565, 25497208, 15024742, 20517649, 20082719, 12515040, 25525159) - |
ATP7B-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 20, 2024 | The ATP7B c.3263T>A variant is predicted to result in premature protein termination (p.Leu1088*). This variant has been reported in multiple individuals with Wilson disease (Deguti et al. 2004. PubMed ID: 15024742, Table 1 and 2; Vrabelova et al. 2005. PubMed ID: 15967699, Table 1; Merle et al. 2010. PubMed ID: 20082719). Furthermore, loss of function variants up and downstream of this variant have been reported to be causative for Wilson disease (e.g. Dong et al. 2016. PubMed ID: 27022412). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at