rs3135867

chr4-1799784-C-Achr4-1799784-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000142.5(FGFR3):c.417C>A(p.Asp139Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. D139A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09151727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.417C>A	p.Asp139Glu	missense_variant	4/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.417C>A	p.Asp139Glu	missense_variant	4/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460676 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.017
Dann	Benign	0.94
DEOGEN2	Uncertain	0.51	D;T;.;.;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.81	T;T;T;T;T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.092	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.86	L;.;L;L;.;L
MutationTaster	Benign	0.88	N;N;N;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.3	N;N;N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.29	T;T;T;T;.;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.0030	B;P;B;P;.;P
Vest4		0.16
MutPred		0.28		Gain of solvent accessibility (P = 0.4067);Gain of solvent accessibility (P = 0.4067);Gain of solvent accessibility (P = 0.4067);Gain of solvent accessibility (P = 0.4067);Gain of solvent accessibility (P = 0.4067);Gain of solvent accessibility (P = 0.4067);
MVP		0.76
MPC		0.28
ClinPred		0.44	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.14

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

Other links and lift over

dbSNP: rs3135867; hg19: chr4-1801511; COSMIC: COSV105835184; COSMIC: COSV105835184;