rs78311289

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000142.5(FGFR3):c.1948A>C(p.Lys650Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K650E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.01

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:

FGFR3 (HGNC:):

FGFR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a mutagenesis_site Constitutively activated kinase. (size 0) in uniprot entity FGFR3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000142.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-1806162-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 4-1806162-A-C is Pathogenic according to our data. Variant chr4-1806162-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 16348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1806162-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5 linkuse as main transcript	c.1948A>C	p.Lys650Gln	missense_variant	14/18	ENST00000440486.8	NP_000133.1	P22607-1Q0IJ44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 linkuse as main transcript	c.1948A>C	p.Lys650Gln	missense_variant	14/18	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249076

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.0000625

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460700

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypochondroplasia

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474) is suspected to be due to variants with a loss of function and dominant negative mechanism, respectively (PMID: 25614871, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (2 heterozygotes, 0 homozygote). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories. This variant has also been observed in multiple unrelated heterozygous individuals with hypochondroplasia and acanthosis nigricans, as well as hyperinsulinemia in one case (PMID: 31708465, 30168875, 21510009, 16912704, 18000903, 20453470, 11055896). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jun 02, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	Greater likelihood of developing acanthosis nigricans [Berk et al 2010, Blomberg et al 2010] -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 22, 2023	PS4, PM1, PM2, PM5, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 16348). This missense change has been observed in individual(s) with hypochondroplasia with or without acanthosis nigricans and/or hyperinsulinemia (PMID: 20453470). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2007	- -

Malignant tumor of urinary bladder

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2007

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2023

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 650 of the FGFR3 protein (p.Lys650Gln). This variant is present in population databases (rs78311289, gnomAD 0.007%). This missense change has been observed in individual(s) with hypochondroplasia with or without acanthosis nigricans and/or hyperinsulinemia (PMID: 11055896, 16912704, 20453470, 21510009). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16348). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 11055896). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.86

D;D;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;.

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

0.82

L;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.6

D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.90

MutPred

0.99

Loss of catalytic residue at K650 (P = 0.0471);.;.;.;.;

MVP

0.94

MPC

2.3

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.69

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