rs75790268
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_000142.5(FGFR3):c.1123G>T(p.Gly375Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G375G) has been classified as Likely benign.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.1123G>T | p.Gly375Cys | missense_variant | 9/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1123G>T | p.Gly375Cys | missense_variant | 9/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460664Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726650
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 03, 2023 | Experimental studies have shown that this missense change affects FGFR3 function (PMID: 9857065, 22529939). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae 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 FGFR3 protein function. ClinVar contains an entry for this variant (Variation ID: 16330). This missense change has been observed in individuals with clinical features of achondroplasia (PMID: 7649548, 7758520, 10893668). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 375 of the FGFR3 protein (p.Gly375Cys). - |
Achondroplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at