4-1806164-G-C

Position:

chr4-1806164-G-C

Variant summary

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

The NM_000142.5(FGFR3):c.1950G>C(p.Lys650Asn) 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 1,460,674 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.76

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 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, 0.984

PP5

Variant 4-1806164-G-C is Pathogenic according to our data. Variant chr4-1806164-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1806164-G-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.1950G>C	p.Lys650Asn	missense_variant	14/18	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.1950G>C	p.Lys650Asn	missense_variant	14/18	5	NM_000142.5	ENSP00000414914	P4	P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249060

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135152

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:

1460674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726660

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 650 of the FGFR3 protein (p.Lys650Asn). This variant is present in population databases (rs28928868, gnomAD 0.007%). This missense change has been observed in individuals with hypochondroplasia (PMID: 11055896). ClinVar contains an entry for this variant (Variation ID: 16347). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. This variant disrupts the p.Lys650 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11055896, 16912704, 18583390, 20453470). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2023	Published functional studies demonstrate a damaging effect as K650N significantly increased constitutive kinase activation in the mutant protein but to a lesser degree than those K650 variants associated with more severe phenotypes (PMID: 11055896); Observed in multiple unrelated families with hypochondroplasia whose clinical features, including radiographic findings and short stature, are on the milder end of the FGFR3 spectrum (PMID: 11055896); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17103447, 17561467, 19855393, 15863034, 20453470, 16912704, 17320202, 26152202, 17509076, 19066716, 26686047, 33726816, 11055896) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 06, 2017	- -

Hypochondroplasia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;D;.

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.61

N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.4

D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.95

MutPred

0.96

Gain of ubiquitination at K649 (P = 0.0444);.;.;.;.;

MVP

0.94

MPC

2.4

ClinPred

0.99

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.83

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