X-133692502-A-G
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_004484.4(GPC3):c.1167-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,201,309 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,621 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_004484.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPC3 | NM_004484.4 | c.1167-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000370818.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPC3 | ENST00000370818.8 | c.1167-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004484.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00294 AC: 331AN: 112673Hom.: 2 Cov.: 24 AF XY: 0.00276 AC XY: 96AN XY: 34799
GnomAD3 exomes AF: 0.00251 AC: 458AN: 182449Hom.: 0 AF XY: 0.00243 AC XY: 163AN XY: 67141
GnomAD4 exome AF: 0.00451 AC: 4907AN: 1088583Hom.: 9 Cov.: 27 AF XY: 0.00430 AC XY: 1525AN XY: 354389
GnomAD4 genome AF: 0.00293 AC: 330AN: 112726Hom.: 2 Cov.: 24 AF XY: 0.00275 AC XY: 96AN XY: 34862
ClinVar
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 14, 2018 | Variant summary: GPC3 c.1167-8T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 199497 control chromosomes in the gnomAD database, including 1 homozygote and 179 hemizygotes. The observed variant frequency is approximately 39459-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in GPC3 causing Wilms Tumor, Type 1 phenotype (6.3e-08), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1167-8T>C in individuals affected with Wilms Tumor, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2017 | - - |
GPC3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 26, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
Wilms tumor 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at