rs121913116
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000142.5(FGFR3):c.251C>T(p.Ser84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S84S) has been classified as Likely benign.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 84 of the FGFR3 protein (p.Ser84Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FGFR3-related conditions (PMID: 16912704, 36373817, 36714562; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as c.250C>T. ClinVar contains an entry for this variant (Variation ID: 16358). Invitae Evidence 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 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. 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. -
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Achondroplasia Pathogenic:2
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has not been seen in the gnomAD database (http://gnomad.broadinstitute.org/) but has been previously reported in a three-generation family with hypochondroplasia [PMID 16912704] and in a two-generation family with short stature (http://pdf.medrang.co.kr/JGM/2016/013/JGM-13-046.pdf) -
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Hypochondroplasia Pathogenic:1
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Achondroplasia;C0265269:Levy-Hollister syndrome;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at