rs28931615
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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
NM_000142.5 missense
Scores
6
6
7
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a transmembrane_region Helical (size 20) 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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | c.1172C>A | p.Ala391Glu | missense_variant | 9/18 | ENST00000440486.8 | NP_000133.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | c.1172C>A | p.Ala391Glu | missense_variant | 9/18 | 5 | NM_000142.5 | ENSP00000414914 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
34
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| 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 | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2021 | - - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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 | 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) - |
Crouzon syndrome-acanthosis nigricans syndrome Pathogenic:6
| 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, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2007 | - - |
| 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 | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 20, 2016 | - - |
| 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 - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;T;D
Sift4G
Benign
T;T;T
Polyphen
P;P;P
Vest4
MutPred
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP
MPC
0.90
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at