Variant 4-1804362-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000142.5(FGFR3):c.1108G>T(p.Gly370Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G370S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 2.49

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]

FGFR3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 4-1804362-G-T is Pathogenic according to our data. Variant chr4-1804362-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804362-G-T is described in Lovd as [Pathogenic]. Variant chr4-1804362-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5 linkuse as main transcript	c.1108G>T	p.Gly370Cys	missense_variant	9/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 linkuse as main transcript	c.1108G>T	p.Gly370Cys	missense_variant	9/18	5	NM_000142.5	ENSP00000414914	P4	P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2022	This missense change has been observed in individual(s) with thanatophoric dysplasia type 1 (PMID: 8845844, 9790257, 24863959, 25614871). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 370 of the FGFR3 protein (p.Gly370Cys). ClinVar contains an entry for this variant (Variation ID: 16359). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 12009017). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	Published functional studies demonstrate p.(G370C) results in spontaneous disulfide bond-mediated dimerization of the FGFR3 protein independent of ligand stimulation that subsequently leads to constitutive activation of the receptor (Adar et al., 2002; You et al., 2007); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8845844, 15772091, 10471491, 25157968, 9790257, 12009017, 16841094, 19752524, 25728633, 25614871, 27028100, 28249712, 28254233, 10696568, 11745189, 24863959, 20301540, 19381019, 17845056) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2020	The FGFR3 c.1108G>T; p.Gly370Cys variant (rs121913479) has been described in several individuals with thanatophoric dysplasia (TD), type I (Rousseau 1996, Katsumata 1998, Xue 2014). It is reported as pathogenic in ClinVar (Variation ID: 16359) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional studies have indicated the p.Gly370Cys variant promotes ligand-independent FGFR3 correct spatial dimerization that results in constitutive ligand independent phosphorylation of MAPK and c-fos transcription (Adar 2002). Based on available formation, this variant is considered pathogenic. REFERENCES Adar R et al. Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. J Bone Miner Res. 2002;17(5): 860-868. Katsumata N et al. G370C mutation in the FGFR3 gene in a Japanese patient with thanatophoric dysplasia. Endocrin J 1998; 45 Suppl:S171-S174. Rousseau F et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet 1996; 5(4):509-512. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med 2014; 2(6): 497-503. -

Thanatophoric dysplasia type 1

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jul 06, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Dec 05, 2022	- -

Thanatophoric dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Jan 10, 2024

- -

Epidermal nevus

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2006

- -

Urinary bladder carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Achondroplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Uncertain

0.80

D;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.9

L;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

N;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.083

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.0060

B;D;B

Vest4

0.83

MutPred

0.81

Loss of disorder (P = 0.0082);Loss of disorder (P = 0.0082);.;

MVP

0.88

MPC

0.31

ClinPred

0.58

GERP RS

2.7

Varity_R

0.25

gMVP

0.69

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over