rs587778353

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

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56
Variant links:
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]

Genome browser will be placed here

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
FGFR3NM_000142.5 linkuse as main transcriptc.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
FGFR3ENST00000440486.8 linkuse as main transcriptc.599G>A p.Arg200His missense_variant 5/185 NM_000142.5 ENSP00000414914 P4P22607-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1418302
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
701576
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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 submitterclinical testingPreventionGenetics, part of Exact SciencesDec 01, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D;T;.;.;T;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;.;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.097
D
MutationAssessor
Uncertain
2.2
M;.;M;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;N;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.9
D;D;D;D;.;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.023
D;D;D;D;.;D;D
Sift4G
Uncertain
0.037
D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;.;D;.
Vest4
0.78
MutPred
0.86
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
0.94
MPC
1.1
ClinPred
0.99
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.51
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587778353; hg19: chr4-1803247; COSMIC: COSV53390730; COSMIC: COSV53390730; API