rs587778776

chr4-1804396-T-Achr4-1804396-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000142.5(FGFR3):c.1142T>A(p.Val381Glu) 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. 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. V381G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346

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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1142T>A	p.Val381Glu	missense_variant	9/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1142T>A	p.Val381Glu	missense_variant	9/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.83	D;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.059	T;D;D
Polyphen		0.28	B;P;B
Vest4		0.81
MutPred		0.87		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;
MVP		0.83
MPC		0.58
ClinPred		0.36	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587778776; hg19: chr4-1806123;