13-51937493-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_000053.4(ATP7B):c.3886G>A(p.Asp1296Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1296G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3886G>A | p.Asp1296Asn | missense_variant | 18/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3886G>A | p.Asp1296Asn | missense_variant | 18/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000200 AC: 50AN: 249436Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 135332
GnomAD4 exome AF: 0.000152 AC: 222AN: 1461708Hom.: 0 Cov.: 35 AF XY: 0.000140 AC XY: 102AN XY: 727140
GnomAD4 genome AF: 0.000171 AC: 26AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74482
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:4Uncertain:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2023 | Variant summary: ATP7B c.3886G>A (p.Asp1296Asn) results in a conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) 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 0.0002 in 249436 control chromosomes (i.e. 50 / 249436 alleles) in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0054), allowing no conclusion about variant significance. c.3886G>A has been reported in the literature in multiple individuals affected with Wilson Disease, including at least three homozygotes (Knuutinen_2021, Sipila_2020) and several compound heterozygous patients diagnosed in the presymptomatic stage (e.g. Ohya_2002, Owada_2002, Nakayama_2008, Lee_2011). 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. Six other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 18, 2018 | The ATP7B c.3886G>A (p.Asp1296Asn) variant is a missense variant that has been reported in at least two studies and is found in a compound heterozygous state in three individuals from two families, including two brothers, with presymptomatic Wilson disease (Ohya et al. 2002; Nakayama et al. 2008). In each family an unaffected parent was heterozygous for the p.Asp1296Asn variant. This variant was reported in one of 50 controls and is reported at a frequency of 0.001815 in the European (Finnish) population of the Exome Aggregation Consortium (Lin et al. 2010). The evidence for this variant is limited. The p.Asp1296Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces aspartic acid with asparagine at codon 1296 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in individuals affected with Wilson disease (PMID: 32618023, 33948933) and in the compound heterozygous state in individuals presymptomatic for Wilson disease (PMID: 11954751, 12032531, 18424137). This variant has been detected in an individual with cancer (PMID: 20045993) and in unaffected populations (PMID: 20465995, 21707886, 33260258). This variant has been identified in 56/280818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 25, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1296 of the ATP7B protein (p.Asp1296Asn). This variant is present in population databases (rs199821556, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11954751, 12032531, 18424137, 21707886, 32618023). 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: 161207). 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%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 23, 2022 | PP1, PP3, PP4, PM2, PM3, PS4_moderate - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21707886, 20465995, 30956230, 32248359, 25637381, 22692182, 12032531, 18424137, 11954751, 30275481) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Feb 09, 2023 | PP3_STR, PM3_STR - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at