4-1804426-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate
The NM_000142.5(FGFR3):c.1172C>T(p.Ala391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. A391E) has been classified as Pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.1172C>T | p.Ala391Val | missense_variant | 9/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1172C>T | p.Ala391Val | missense_variant | 9/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460166Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 726358
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152346Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in association with skeletal dysplasia or craniosynostosis to our knowledge; This variant is associated with the following publications: (PMID: 26517354, 24360661, 7493034, 20199409, 11426459, 10670894) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. 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. This variant disrupts the p.Ala391 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7493034, 8880573, 11426459, 20199409). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt FGFR3 protein function. ClinVar contains an entry for this variant (Variation ID: 809609). This variant is present in population databases (no rsID available, gnomAD 0.0008%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 391 of the FGFR3 protein (p.Ala391Val). - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at