rs121913101
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000142.5(FGFR3):c.2419T>A(p.Ter807ArgextTer101) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FGFR3
NM_000142.5 stop_lost
NM_000142.5 stop_lost
Scores
3
4
7
Clinical Significance
Conservation
PhyloP100: 2.71
Genes affected
FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-1807260-T-A is Pathogenic according to our data. Variant chr4-1807260-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 16335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.25191468).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.2419T>A | p.Ter807ArgextTer101 | stop_lost | 18/18 | ENST00000440486.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.2419T>A | p.Ter807ArgextTer101 | stop_lost | 18/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Thanatophoric dysplasia type 1 Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1995 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;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;C4048328:Cervical cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2022 | Published functional studies demonstrate this variant results in an extended protein which may have a damaging effect by causing a reduced level of glycosylated protein (Bonaventure et al., 2007; Gibbs et al., 2007); Variant resulting in loss of the termination codon leading to protein extension by 101 amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Multiple other variants resulting in loss of termination codon and protein extension reported in association with thanatophoric dysplasia (HGMD); This variant is associated with the following publications: (PMID: 28254233, 17320202, 25614871, 20301540, 17509076, 25728633, 25800480, 34367232, 7647778) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Polyphen
B
Vest4
MutPred
Gain of solvent accessibility (P = 0.0078);
MVP
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at