rs121913482

Positions:

• chr4-1801837-C-G
• chr4-1801837-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000142.5(FGFR3):​c.742C>G​(p.Arg248Gly) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1801837-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.742C>G	p.Arg248Gly	missense_variant, splice_region_variant	7/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.742C>G	p.Arg248Gly	missense_variant, splice_region_variant	7/18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;T;.;.;T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;T;D;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	2.9	M;.;M;M;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;.;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;D;D;T;.;T;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.68	P;D;B;D;.;D;.
Vest4		0.90
MutPred		0.79		Loss of stability (P = 0.0739);Loss of stability (P = 0.0739);Loss of stability (P = 0.0739);Loss of stability (P = 0.0739);Loss of stability (P = 0.0739);Loss of stability (P = 0.0739);.;
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1803564;