rs137853287
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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.2304delβ(p.Met769CysfsTer38) 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 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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: -2.18
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 13-51958361-TG-T is Pathogenic according to our data. Variant chr13-51958361-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 88957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958361-TG-T is described in Lovd as [Pathogenic]. Variant chr13-51958361-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr13-51958361-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2304del | p.Met769CysfsTer38 | frameshift_variant | 8/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.2304del | p.Met769CysfsTer38 | frameshift_variant | 8/21 | 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: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727248
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GnomAD4 genome ? Cov.: 32
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Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Met769Cysfs*38) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 9554743, 16603785). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88957). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This variant deletes 1 nucleotide in exon 8 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 in over 10 individuals affected with autosomal recessive Wilson disease (PMID: 9554743, 23982005, 23159873, 31059521, 35782615), including three individuals in the homozygous state (PMID: 19118915) and three individuals in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 16603785, 25704634, 26799313). This variant has not been identified 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 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2017 | The c.2304delC pathogenic mutation, located in coding exon 8 of the ATP7B gene, results from a deletion of one nucleotide at nucleotide position 2304, causing a translational frameshift with a predicted alternate stop codon (p.M769Cfs*38). This mutation was first reported in an individual with Wilson disease; however, the second ATP7B alteration was not provided (Kim EK et al. Hum. Mutat., 1998;11:275-8). In a cohort of Chinese Han individuals with Wilson disease, this mutation was detected in conjunction with a second ATP7B alteration; however, the phase was not provided (Liu Y et al. Arch. Med. Res., 2015 Feb;46:164-9). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | ATP7B: PVS1, PP1:Strong, PM2, PM3, PP4 - |
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