rs137853283
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.2336G>A(p.Trp779Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,042 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 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 | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2336G>A | p.Trp779Ter | stop_gained | 8/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.2336G>A | p.Trp779Ter | stop_gained | 8/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249424Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135344
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727246
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74322
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 08, 2022 | The ATP7B c.2336G>A; p.Trp779Ter variant (rs137853283) is reported in the literature as one of the most common variants in a Wilson disease cohort study (Vrabelova 2005), and has been described in at least one individual who was homozygous for the variant (Waldenstrom 1996). This variant is also reported in ClinVar (Variation ID: 156284), and is found in the general population with an overall allele frequency of 0.0039% (11/280818 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 to be pathogenic. References: 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. PMID: 15967699. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. PMID: 8938442. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Trp779X variant in ATP7B has been previously reported in several individuals with Wilson disease, including at least 3 homozygotes and 8 compound heterozygotes, and segregated in at least 2 affected family members (Bem 2013, Caca 2001, Coffey 2013, Dong 2016, Moller 2011, Vrabelova 2005, Waldenstrom 1996). It is present in 0.01% (3/25038) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 779, 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, PM3_VeryStrong, PM2, PP1_Moderate. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 30, 2023 | This variant changes 1 nucleotide in exon 8 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 observed in the compound heterozygous state and homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8938442, 11690702, 15202786, 15967699, 18371106, 20958917, 21610751, 23518715, 23982005, 24517292, 27022412), indicating that this variant contributes to disease. This variant has been identified in 11/280818 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 | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Trp779*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 8938442, 23982005; Invitae). ClinVar contains an entry for this variant (Variation ID: 156284). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2017 | Variant summary: The ATP7B c.2336G>A (p.Trp779X) 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. This variant was found in 8/246088 control chromosomes (gnomAD) at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple compound heterozygote and homozygote WD pts have been reported via publications (Vrabelova_2005, Moller_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 03, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 06, 2022 | PP5, PM2, PS4, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | ATP7B: PVS1, PM2, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2021 | 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 significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26207595, 21610751, 28856630, 8938442, 28753182, 30230192, 31144528, 30965071, 23982005, 11690702, 15967699, 15202786) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2017 | The p.W779* pathogenic mutation (also known as c.2336G>A), located in coding exon 8 of the ATP7B gene, results from a G to A substitution at nucleotide position 2336. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation was detected in one homozygous individual with a clinical diagnosis of Wilson disease, who presented at age 18 with moderate neurologic disease (Waldenström E et al. Genomics, 1996 Nov;37:303-9). In two cohorts of individuals with Wilson disease, this mutation was found in greater than 10 alleles; however, complete genotype information was not provided (Gromadzka G et al. Clin. Genet., 2005 Dec;68:524-32; Vrabelova S et al. Mol. Genet. Metab. Jun;86:277-85). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at