4-1804365-A-T

Position:

• chr4-1804365-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000142.5(FGFR3):​c.1111A>T​(p.Ser371Cys) 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 (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.37

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]

ACMG classification

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, 0.962
• PP5: Variant 4-1804365-A-T is Pathogenic according to our data. Variant chr4-1804365-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 16333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804365-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1111A>T	p.Ser371Cys	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	c.1111A>T	p.Ser371Cys	missense_variant	9/18	5	NM_000142.5	ENSP00000414914	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2024	Published functional studies demonstrate ligand-independent, constitutive dimerization and phosphorylation of the MAPK and c-fos pathways (PMID: 17845056, 12009017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22045636, 7773297, 8845844, 25157968, 28249712, 10587515, 12009017, 11181569, 17845056, 34358384) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Thanatophoric dysplasia type 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jun 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1995	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 11, 2019

The FGFR3 c.1111A>T; p.Ser371Cys variant (rs121913484) is a known pathogenic variant causative for thanatophoric dysplasia type I (Tavormina 1995, Karczeski 2013). It is reported as pathogenic in ClinVar (Variation ID 16333) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional studies have indicated the p.Ser371Cys variant promotes ligand-independent FGFR3 correct spatial dimerization that results in constitutive ligand independent phophorylation of MAPK and c-fos transcription (Adar 2002). Based on available information, this variant is considered pathogenic. REFERENCES Adar 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. Karczenski, B and Cutting, GR: Thanatophoric Dysplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2017. 2004 May 21 (updated 2013 Sep 12). Tavormina PL et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 1995; 9(3):321-328. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.92	D;D;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.043	D
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.90	A;A;A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.065	T;T;T
Polyphen		0.97	D;D;D
Vest4		0.82
MutPred		0.80		Loss of disorder (P = 0.0065);Loss of disorder (P = 0.0065);.;
MVP		0.92
MPC		0.89
ClinPred		0.59	D
GERP RS		2.1
Varity_R		0.29
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913484; hg19: chr4-1806092; COSMIC: COSV53390047; COSMIC: COSV53390047;