rs17881656

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000142.5(FGFR3):c.1150T>A(p.Phe384Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,896 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F384L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.767

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a helix (size 24) in uniprot entity FGFR3_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000142.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15758365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.1150T>A	p.Phe384Ile	missense_variant	Exon 9 of 18	ENST00000440486.8	NP_000133.1	P22607-1Q0IJ44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 link	c.1150T>A	p.Phe384Ile	missense_variant	Exon 9 of 18	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250474

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460896

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726770

show subpopulations

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 384 of the FGFR3 protein (p.Phe384Ile). This variant is present in population databases (rs17881656, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.60

D;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.9

L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.056

T;D;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.23

MutPred

0.32

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;

MVP

0.89

MPC

0.39

ClinPred

0.16

GERP RS

3.6

Varity_R

0.24

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over