rs121913116

chr4-1799395-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000142.5(FGFR3):c.251C>T(p.Ser84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S84S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.0340

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant 4-1799395-C-T is Pathogenic according to our data. Variant chr4-1799395-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1799395-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.251C>T	p.Ser84Leu	missense_variant	3/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.251C>T	p.Ser84Leu	missense_variant	3/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achondroplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 30, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has not been seen in the gnomAD database (http://gnomad.broadinstitute.org/) but has been previously reported in a three-generation family with hypochondroplasia [PMID 16912704] and in a two-generation family with short stature (http://pdf.medrang.co.kr/JGM/2016/013/JGM-13-046.pdf) -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Hypochondroplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2006

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 84 of the FGFR3 protein (p.Ser84Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with FGFR3-related conditions (PMID: 16912704, 36373817, 36714562; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.250C>T. ClinVar contains an entry for this variant (Variation ID: 16358). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Achondroplasia;C0265269:Levy-Hollister syndrome;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;.;.;T;.
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.78	T;T;T;T;T;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.;M;M;.;M
MutationTaster	Benign	0.048	A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D;D;D;D;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.024	D;D;D;D;.;D
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.89	P;D;B;D;.;D
Vest4		0.28
MutPred		0.75		Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);Loss of disorder (P = 0.0339);
MVP		0.67
MPC		0.25
ClinPred		0.81	D
GERP RS		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.14
gMVP		0.53

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: rs121913116; hg19: chr4-1801122;