rs587778352

Positions:

• chr4-1799443-C-G
• chr4-1799443-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000142.5(FGFR3):​c.299C>G​(p.Ser100Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.04

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.299C>G	p.Ser100Cys	missense_variant	3/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.299C>G	p.Ser100Cys	missense_variant	3/18	5	NM_000142.5	ENSP00000414914	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;T;.;.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	T;T;T;T;T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;.;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.086	T;D;T;T;.;T
Sift4G	Uncertain	0.055	T;D;T;T;T;T
Polyphen		0.85	P;D;D;D;.;D
Vest4		0.67
MutPred		0.56		Loss of disorder (P = 0.0039);Loss of disorder (P = 0.0039);Loss of disorder (P = 0.0039);Loss of disorder (P = 0.0039);Loss of disorder (P = 0.0039);Loss of disorder (P = 0.0039);
MVP		0.71
MPC		0.92
ClinPred		0.95	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs587778352; hg19: chr4-1801170;