rs121908001
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.2071G>A(p.Gly691Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,660 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: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 7.80
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, 0.976
PP5
Variant 13-51960198-C-T is Pathogenic according to our data. Variant chr13-51960198-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51960198-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2071G>A | p.Gly691Arg | missense_variant | 7/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727144
GnomAD4 exome
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1461660
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31
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727144
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:8
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 24, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 691 of the ATP7B protein (p.Gly691Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 9671269, 17718866, 23389864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3866). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2022 | Variant summary: ATP7B c.2071G>A (p.Gly691Arg) results in a non-conservative amino acid change located in the TM2 domain (Loudianos_1998) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249376 control chromosomes (gnomAD and publication data). c.2071G>A has been reported in the literature in multiple individuals affected with Wilson Disease, including homozygotes (Loudianos_1998, Barada_2007, Couchonnal_2021). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | This missense variant replaces glycine with arginine at codon 691 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies conducted in transfected Chinese hamster ovary cells have shown that this variant results in reduced protein expression and decreased cell growth in the presence of copper (Scvortova 2013). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 9671269, 17718866, 22677543, 23389864, 23551039, 34400371). In several of these individuals, this variant was confirmed to be in the homozygous state or in the compound heterozygous state with a pathogenic variant in the same gene (PMID: 17718866, 23389864, 23551039), indicating that this variant contributes to disease. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Gly691Val, is a pathogenic mutation (Clinvar Variation ID: 555245), indicating that glycine at this position is important for ATP7B protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 17, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;T;D;.;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;B;D;D
Vest4
MutPred
Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at