chr2-222297175-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_181458.4(PAX3):c.124G>C(p.Gly42Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Likely benign.
Frequency
Consequence
NM_181458.4 missense
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 |
---|---|---|---|---|---|---|---|
PAX3 | NM_181458.4 | c.124G>C | p.Gly42Arg | missense_variant | 2/9 | ENST00000392070.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX3 | ENST00000392070.7 | c.124G>C | p.Gly42Arg | missense_variant | 2/9 | 1 | NM_181458.4 | A1 |
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD4 exome AF: 6.92e-7 AC: 1AN: 1445078Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 717486
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Waardenburg syndrome type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Mar 01, 2017 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PAX3 function (PMID: 18325909, 28381738). 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 PAX3 protein function. ClinVar contains an entry for this variant (Variation ID: 488034). This missense change has been observed in individuals with autosomal dominant Waardenburg syndrome (PMID: 28686331, 29407415). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 42 of the PAX3 protein (p.Gly42Arg). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28381738, 34038854, 18325909, 16280008, 8406487, 29407415, 7867071, 28686331) - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at