rs28931615

chr4-1804426-C-Achr4-1804426-C-Gchr4-1804426-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000142.5(FGFR3):c.1172C>A(p.Ala391Glu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A391V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 1.43

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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 4-1804426-C-A is Pathogenic according to our data. Variant chr4-1804426-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804426-C-A is described in Lovd as [Pathogenic]. Variant chr4-1804426-C-A is described in Lovd as [Likely_pathogenic]. Variant chr4-1804426-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1172C>A	p.Ala391Glu	missense_variant	9/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1172C>A	p.Ala391Glu	missense_variant	9/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The c.1172C>A variant, located in exon 9 of FGFR3, results in a substitution of alanine with glutamic acid at position 391 of the protein. This is a recurrent pathogenic variant that has previously been reported in several individuals with Crouzon syndrome with acanthosis nigricans (PMID: 7493034, 8880573, 17935505, 31016899, NBK1455). In these reports, common clinical features include craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia or stenosis, hydrocephalus, and acanthosis nigricans. Other features such as Chiari malformations, vertebral anomalies, and subtle skeletal findings have also been reported. This variant is absent from large population cohorts (0 of >281,000 alleles; Genome Aggregation Database v2.1). The Ala391Glu change has been experimentally demonstrated to cause an increase in FGFR3 activation by means of FGFR3 dimer stabilization and phosphorylation of critical tyrosines in the FGFR3 activation loop (PMID: 23437153). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Published functional studies demonstrate a lower expression of the protein in comparison to wild-type and an increase in the phosphorylation level (Chen et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23727984, 9857065, 18976668, 23437153, 21536014, 27228464, 17935505, 27181494, 29620724, 8880573, 31016899, 31837199, 10670894, 7493034, 11426459, 20199409) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 24, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 391 of the FGFR3 protein (p.Ala391Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Crouzon syndrome with acanthosis nigricans (CSAN) (PMID: 7493034, 8880573, 11426459, 20199409). ClinVar contains an entry for this variant (Variation ID: 16329). 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. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 18976668, 21536014, 23437153). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Crouzon syndrome-acanthosis nigricans syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 10, 2023	Criteria applied: PS2,PS4,PS3_MOD,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 2-year-old female with Crouzon syndrome -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 24, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 20, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2016

- -

Carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Craniosynostosis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;T;.
Eigen	Benign	0.037
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.97	A;A;A;A;A;A
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D;T;D
Sift4G	Benign	0.073	T;T;T
Polyphen		0.50	P;P;P
Vest4		0.79
MutPred		0.89		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.91
MPC		0.90
ClinPred		0.84	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
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

Other links and lift over

dbSNP: rs28931615; hg19: chr4-1806153; COSMIC: COSV53391630; COSMIC: COSV53391630;