chr13-51958372-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.2294A>G(p.Asp765Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. D765N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2294A>G | p.Asp765Gly | missense_variant | 8/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.2294A>G | p.Asp765Gly | missense_variant | 8/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74430
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:4
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 | Apr 08, 2016 | Variant summary: The ATP7B c.2294A>G variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was not observed in controls (1000 Gs, ESP, or ExAC). Multiple publications cite the variant in affected individuals and authors indicate the variant is located in the predicted transmembrane helical hairpin N-terminal to the transduction domain, therefore it is predicted to be important for proper protein function (Gu_2003). Multiple publications and a database cite the variant to be "pathogenic/disease variant." In addition, another variant affecting this amino acid, c.2293G>A, p.Asp765Asn has been reported as a pathogenic variant. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 27, 2018 | The ATP7B c.2294A>G; p.Asp765Gly variant is reported in the literature in multiple individuals affected with Wilson disease and has been observed in trans to another pathogenic ATP7B variant in several affected individuals (Gu 2003, Gu 2013, Wang 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 495406), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant at this codon (p.Asp765Asn) has been reported in individuals with Wilson disease and is considered pathogenic (Figus 1995, Kalinsky 1998), consistent with functional assays that indicate aberrant localization and decreased transport activity (Forbes 2000, Huster 2012). The aspartate at codon 765 is highly conserved and both computational analyses (SIFT, PolyPhen-2) and structural modeling approaches predict that the p.Asp765Gly variant is deleterious (Schushan 2012, Squitti 2014). Based on available information, this variant is considered to be likely pathogenic. References: Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995 Dec;57(6):1318-24. Forbes JR and Cox DW. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet. 2000 Aug 12;9(13):1927-35. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Gu YH et al. Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet. 2003 Dec;64(6):479-84. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. Schushan M et al. A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. Metallomics. 2012 Jul;4(7):669-78. Squitti R et al. In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure. Biometals. 2014 Feb;27(1):53-64. Wang LH et al. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet. 2011 Sep;56(9):660-5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp765 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9482578, 15024742, 20517649, 21682854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 495406). This missense change has been observed in individual(s) with Wilson disease (PMID: 23843956, 30384382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 765 of the ATP7B protein (p.Asp765Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at