rs752850609
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000053.4(ATP7B):c.1847G>A(p.Arg616Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,058 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 (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 7.50
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.
PM1
In a domain HMA 6 (size 66) in uniprot entity ATP7B_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000053.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.858
PP5
Variant 13-51964894-C-T is Pathogenic according to our data. Variant chr13-51964894-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 552606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51964894-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.1847G>A | p.Arg616Gln | missense_variant | 5/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.1847G>A | p.Arg616Gln | missense_variant | 5/21 | 1 | NM_000053.4 | ENSP00000242839.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249570Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135404
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727242
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74402
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:12
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 30, 2018 | Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246238 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.9e-05 vs 0.0054), allowing no conclusion about variant significance. c.1847G>A has been reported in the literature in multiple individuals affected with Wilson Disease as both a compound heterozygous and homozygous allele (Loudianos_2003, Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ATP7B protein (p.Arg616Gln). This variant is present in population databases (rs752850609, gnomAD 0.009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 12885331, 21610751, 22735241, 26799313). ClinVar contains an entry for this variant (Variation ID: 552606). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 06, 2024 | This missense variant replaces arginine with glutamine at codon 616 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 10502777, 12885331, 16283883, 17264425, 18286826, 18034201, 21610751, 22735241, 23518715, 23789284, 26799313). In many of these affected individuals, this variant has been determined to be homozygous or compound heterozygous with another pathogenic variant in the same gene (PMID: 12885331, 17264425, 21610751, 22735241, 23518715, 26799313). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 12/249570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg616Trp, is classified as pathogenic (Clinvar Variation ID: 863093), indicating that arginine at this position is important for ATP7b protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM5_Supporting+PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 09, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 14, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
not provided Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16283883, 18286826, 17264425, 32118851, 23789284, 23518715, 12885331, 22735241, 18371106, 18034201, 10502777, 20517649, 21610751, 17919502, 30702195, 26799313, 35271763) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;T;D;D;.;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;D;D;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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