rs587778353
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000142.5(FGFR3):c.599G>A(p.Arg200His) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
FGFR3
NM_000142.5 missense
NM_000142.5 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 9.56
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 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGFR3 | NM_000142.5 | c.599G>A | p.Arg200His | missense_variant | 5/18 | ENST00000440486.8 | NP_000133.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR3 | ENST00000440486.8 | c.599G>A | p.Arg200His | missense_variant | 5/18 | 5 | NM_000142.5 | ENSP00000414914 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1418302Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 701576
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1418302
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
701576
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
FGFR3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 01, 2022 | The FGFR3 c.599G>A variant is predicted to result in the amino acid substitution p.Arg200His. To our knowledge, this variant has not been reported in the literature in individuals with FGFR3-related disorders or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;M;.;M;.
MutationTaster
Benign
D;D;D;D;N;N
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;D;D;D;.;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);.;
MVP
MPC
1.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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