rs121913113
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000142.5(FGFR3):c.1862G>A(p.Arg621His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.1862G>A | p.Arg621His | missense_variant | 14/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1862G>A | p.Arg621His | missense_variant | 14/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461266Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726964
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 621 of the FGFR3 protein (p.Arg621His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with campylodactyly, tall stature and sensorineural deafness (PMID: 17033969, 27139183). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1915G>A. ClinVar contains an entry for this variant (Variation ID: 16355). 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. For these reasons, this variant has been classified as Pathogenic. - |
Camptodactyly-tall stature-scoliosis-hearing loss syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at