rs78311289
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):āc.1948A>Cā(p.Lys650Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,700 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K650E) has been classified as 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.1948A>C | p.Lys650Gln | missense_variant | 14/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.1948A>C | p.Lys650Gln | missense_variant | 14/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249076Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135148
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460700Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726664
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Hypochondroplasia Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | Greater likelihood of developing acanthosis nigricans [Berk et al 2010, Blomberg et al 2010] - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 2007 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jan 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jun 02, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Dec 22, 2023 | PS4, PM1, PM2, PM5, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 16348). This missense change has been observed in individual(s) with hypochondroplasia with or without acanthosis nigricans and/or hyperinsulinemia (PMID: 20453470). - |
Malignant tumor of urinary bladder Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 2007 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 650 of the FGFR3 protein (p.Lys650Gln). This variant is present in population databases (rs78311289, gnomAD 0.007%). This missense change has been observed in individual(s) with hypochondroplasia with or without acanthosis nigricans and/or hyperinsulinemia (PMID: 11055896, 16912704, 20453470, 21510009). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16348). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 11055896). For these reasons, this variant has been classified as Pathogenic. - |
Urinary bladder carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Acanthosis nigricans Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at