chrX-133753638-A-C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_004484.4(GPC3):c.876T>G(p.Ile292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,666 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I292T) has been classified as Uncertain significance.
Frequency
Consequence
NM_004484.4 missense
Scores
Clinical Significance
Conservation
Publications
- Simpson-Golabi-Behmel syndromeInheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- Simpson-Golabi-Behmel syndrome type 1Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD2 exomes AF: 0.0000327 AC: 6AN: 183334 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1097666Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 363036 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Wilms tumor 1 Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 292 of the GPC3 protein (p.Ile292Met). This variant is present in population databases (rs61754633, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 843877). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GPC3 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at