13-51934941-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000053.4(ATP7B):c.4213G>A(p.Gly1405Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1405G) has been classified as Likely benign.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.4213G>A | p.Gly1405Ser | missense_variant | 21/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.4213G>A | p.Gly1405Ser | missense_variant | 21/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152214Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000363 AC: 9AN: 247972Hom.: 0 AF XY: 0.0000594 AC XY: 8AN XY: 134694
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461788Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 727200
GnomAD4 genome AF: 0.000243 AC: 37AN: 152332Hom.: 1 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74492
ClinVar
Submissions by phenotype
Wilson disease Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 30, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1405 of the ATP7B protein (p.Gly1405Ser). This variant is present in population databases (rs189601972, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 444316). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 15, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces glycine with serine at codon 1405 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 not been reported in individuals affected with Wilson disease in the literature. This variant has been identified in 11/279374 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. - |
not provided Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 25, 2024 | The p.Gly1405Ser variant in ATP7B has not been reported in individuals with ATP7B-associated disorder(s). This variant has been identified in 0.18% (28/15284) of Latino/Admixed American chromosomes, including 1 homozygotes, by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 444316). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ATP7B: PM3:Strong, PM2, PP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 04, 2018 | The ATP7B c.4213G>A; p.Gly1405Ser variant (rs189601972), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 444316). This variant is found in the general population with an overall allele frequency of 0.004% (11/275580 alleles) in the Genome Aggregation Database. The glycine at codon 1405 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Gly1405Ser variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 09, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: ATP7B c.4213G>A (p.Gly1405Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247972 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4213G>A has been reported in the literature in at-least one individual from a Wilson Disease patient cohort with at least 1 variant in ATP7B (example: Nayagam_2023). This report does not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24253677, 36096368). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at