4-1804426-C-A

Variant names:

• chr4-1804426-C-A
• rs28931615
• NM_000142.5:c.1172C>A

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 (★★).

• 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 helix (size 24) in uniprot entity FGFR3_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) 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 rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1172C>A	p.Ala391Glu	missense_variant	Exon 9 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1172C>A	p.Ala391Glu	missense_variant	Exon 9 of 18	5	NM_000142.5	ENSP00000414914.2

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

Crouzon syndrome-acanthosis nigricans syndrome Pathogenic:7

Oct 20, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2009

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2,PS4,PS3_MOD,PM2_SUP,PP3 -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both gain and loss of function are known mechanisms of disease in this gene. Gain of function variants in this gene have been associated with autosomal dominant skeletal dysplasias, while loss of function variants have been associated with autosomal recessive CATSHL syndrome (PMID: 25614871). The disease mechanism for autosomal dominant LADD syndrome is not clearly established. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (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 syndrome patients, even within the same family (PMID: 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with craniosynostosis, Crouzon syndrome with acathosis nigricans and one de novo individual with Pfeiffer syndrome type 3 (ClinVar, LOVD, PMID: 31016899). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:6

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence 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 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. -

Nov 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 18, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Craniosynostosis syndrome Pathogenic:1

Jul 27, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
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;