rs769484789
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.3784G>T(p.Val1262Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,172 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.86
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.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 13-51937595-C-A is Pathogenic according to our data. Variant chr13-51937595-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51937595-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3784G>T | p.Val1262Phe | missense_variant | 18/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3784G>T | p.Val1262Phe | missense_variant | 18/21 | 1 | NM_000053.4 | ENSP00000242839.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249584Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135410
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461892Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727246
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74396
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1262 of the ATP7B protein (p.Val1262Phe). This variant is present in population databases (rs769484789, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson's disease (PMID: 10544227, 20485189; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 19937698). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The p.Val1262Phe variant in ATP7B has been reported in at least 4 individuals with Wilson disease and segregated with disease in 1 affected individual from 1 family (Loudianos 1999 PMID: 10544227, Shim 2018 PMID: 29930488, Song 2022 PMID: 35388883). It has also been identified in 0.001% (1/68052) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 550902). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant reduces ATP7B protein expression (van den Berghe 2009 PMID: 19937698); however, these types of assays may not accurately represent biological function. 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: PM3, PM2_Supporting, PP1, PP3, PS3_Supporting. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 18, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This variant was detected in multiple affected individuals as homozygous or as compound heterozygous (in trans) with a pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 10544227, 20485189, 20958917, 29930488, 35388883). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 19937698, 35388883). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D
Vest4
MutPred
Gain of catalytic residue at V1262 (P = 0.0759);.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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