rs137853280
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.1708-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000053.4 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1708-1G>C | splice_acceptor_variant | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.1708-1G>C | splice_acceptor_variant | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249468Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135370
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727208
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74428
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:9
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 | Jul 23, 2018 | Variant summary: ATP7B c.1708-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant determines exon 5 skipping (Tsai_1999). The variant allele was found at a frequency of 2.9e-05 in 277094 control chromosomes (gnomAD). The variant, c.1708-1G>C, has been reported in the literature in multiple individuals affected with Wilson Disease (Coffey_2013, Hua_2016, Mukherjee_2014, Tsai_1999). 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 | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 04, 2022 | NM_000053.3(ATP7B):c.1708-1G>C is a canonical splice variant classified as pathogenic in the context of Wilson disease. c.1708-1G>C has been observed in cases with relevant disease (PMID: 24094725, 9829905). Functional assessments of this variant are available in the literature (PMID: 9829905). c.1708-1G>C has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, NM_000053.3(ATP7B):c.1708-1G>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 29, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change affects an acceptor splice site in intron 4 of the ATP7B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs137853280, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 9829905, 27398169). This variant is also known as c.1711-1G>C. ClinVar contains an entry for this variant (Variation ID: 3850). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2019 | - - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2023 | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Also known as c.1711-1 G>C; This variant is associated with the following publications: (PMID: 35470480, 30655162, 34324271, 35446965, 30275481, 30291343, 9829905, 18034201, 22735241, 23518715, 20931554, 24094725, 11060541, 11405812, 23843956, 21034864, 23275100, 24146181, 7626145, 27398169, 33763395) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | ATP7B: PVS1, PM2, PM3:Supporting, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at