Variant rs1553842213 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000142.5(FGFR3):c.109G>A(p.Glu37Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,245,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense, splice_region

Scores

Splicing: ADA: 0.9938

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.04

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.

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 linkuse as main transcript	c.109G>A	p.Glu37Lys	missense_variant, splice_region_variant	2/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 linkuse as main transcript	c.109G>A	p.Glu37Lys	missense_variant, splice_region_variant	2/18	5	NM_000142.5	ENSP00000414914	P4	P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1245626

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

610588

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:

0.0000141

Gnomad4 OTH exome

AF:

0.0000200

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 07, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T;.;.;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.94

D;D;D;D;D;.

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.44

T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.2

L;.;L;L;.;L

MutationTaster

Benign

0.87

D;D;D;D;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.0

N;N;N;N;.;N

REVEL

Benign

0.27

Sift

Benign

0.34

T;D;T;T;.;T

Sift4G

Benign

0.86

T;T;T;T;T;T

Polyphen

0.18

B;D;B;D;.;D

Vest4

0.48

MutPred

0.41

Gain of ubiquitination at E37 (P = 0.0077);Gain of ubiquitination at E37 (P = 0.0077);Gain of ubiquitination at E37 (P = 0.0077);Gain of ubiquitination at E37 (P = 0.0077);Gain of ubiquitination at E37 (P = 0.0077);Gain of ubiquitination at E37 (P = 0.0077);

MVP

0.92

MPC

0.36

ClinPred

0.11

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.054

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.12

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