rs121913107
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):āc.1619A>Cā(p.Asn540Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,880 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540D) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.1619A>C | p.Asn540Thr | missense_variant | 12/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1619A>C | p.Asn540Thr | missense_variant | 12/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460880Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726800
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2020 | 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. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25728633, 9452043, 30048571, 30681580, 35438268) - |
Hypochondroplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at