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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 Genomes 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

Scores

6
6
7

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 1.43
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]

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ACMG classification

Classification made for transcript

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
FGFR3NM_000142.5 linkuse as main transcriptc.1172C>A p.Ala391Glu missense_variant 9/18 ENST00000440486.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FGFR3ENST00000440486.8 linkuse as main transcriptc.1172C>A p.Ala391Glu missense_variant 9/185 NM_000142.5 P4P22607-1

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
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 24, 2023This 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 submitterclinical testingSeattle 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, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 01, 2021Published 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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Crouzon syndrome-acanthosis nigricans syndrome Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 10, 2023Criteria applied: PS2,PS4,PS3_MOD,PM2_SUP,PP3 -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2007- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalDec 24, 2009- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 01, 2017This 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 submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaOct 20, 2016- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Medical Genetics, Oslo University Hospital-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 18, 2016- -
Carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Craniosynostosis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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