rs746485916
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000053.4(ATP7B):c.3121C>T(p.Arg1041Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,906 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3121C>T | p.Arg1041Trp | missense_variant | 14/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3121C>T | p.Arg1041Trp | missense_variant | 14/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 248998Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135292
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727214
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74286
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:8
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | Across a selection of the available literature, the ATP7B c.3121C>T (p.Arg1041Trp) missense variant has been identified in a compound heterozygous state in four patients with Wilson disease, including two siblings (Loudianos et al. 1998; Loudianos et al. 1999; Deguti et al. 2004; Kucinskas et al. 2008). Simsek Papur et al. (2013) and Guggilla et al. (2015) also identified the p.Arg1041Trp variant in four alleles in a cohort of affected individuals where zygosity was not stated. Coffey et al. (2013) reported the p.Arg1041Trp variant in a heterozygous state in one of 5,162 controls and it is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Experiments in yeast revealed that the p.Arg1041Trp variant was able to complement copper transport function, however the evidence is limited as other aspects of protein function were not evaluated (Hsi et al. 2008). Based on the available evidence, the p.Arg1041Trp variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1041 of the ATP7B protein (p.Arg1041Trp). This variant is present in population databases (rs746485916, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 15024742, 15967699, 18855987, 20931554, 21610751, 22677543, 25982861, 27022412; 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: 312384). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 18203200). This variant disrupts the p.Arg1041 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 10194254), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces arginine with tryptophan at codon 1041 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). This variant alters a conserved arginine residue in the ATP nucleotide binding domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). It has been shown that this variant does not substantially affect ATP7B protein function in a yeast study (PMID: 18203200). This variant has been reported in almost twenty individuals affected with autosomal recessive Wilson disease (PMID: 9671269, 10544227, 15024742, 15205742, 15967699, 18855987, 20517649, 20931554, 21610751, 22677543, 23333878, 23518715, 25982861, 27022412). This variant was observed in the compound heterozygous state with a second pathogenic variant in at least six affected individuals and in the homozygous state in at least five affected individuals (PMID: 10544227, 15205742, 18855987, 20517649, 21610751, 23518715, 25982861), indicating that this variant contributes to disease. This variant has been identified in 8/248998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Aug 29, 2022 | PM3, PS3, PP3, PS4, PM2_SUP - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9671269, 31589614, 24253677, 18203200, 22692182, 27022412, 25982861, 31746411, 29930488, 23518715, 21610751, 34400371, 15967699, 15024742, 20931554, 22677543, 23333878, 18855987, 36360177, 33640437, 32770663, 34470610) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 17, 2023 | PP3, PP4, PM2, PM3, PM5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at