rs121918497
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000141.5(FGFR2):āc.866A>Cā(p.Gln289Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
FGFR2
NM_000141.5 missense
NM_000141.5 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 6.27
Genes affected
FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists 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 is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000141.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, FGFR2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 10-121520052-T-G is Pathogenic according to our data. Variant chr10-121520052-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520052-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGFR2 | NM_022970.4 | c.866A>C | p.Gln289Pro | missense_variant | 7/18 | ENST00000457416.7 | |
FGFR2 | NM_000141.5 | c.866A>C | p.Gln289Pro | missense_variant | 7/18 | ENST00000358487.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000457416.7 | c.866A>C | p.Gln289Pro | missense_variant | 7/18 | 1 | NM_022970.4 | P4 | |
FGFR2 | ENST00000358487.10 | c.866A>C | p.Gln289Pro | missense_variant | 7/18 | 1 | NM_000141.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 exome
AF:
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1
AN:
1461886
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727244
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pfeiffer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 17, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2023 | Not observed in large population cohorts (gnomAD); Within the immunoglobulin-like domain 3, in which pathogenic variants are typically associated with craniosynostosis phenotypes (Kan et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9385368, 23754559, 19066959, 7655462, 11781872, 8644708, 30355600, 7581378, 10712195, 16526917, 22355256, 24656465, 11173845, 12884424, 16470531, 32369273, 16418739, 35591945) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 12, 2018 | DNA sequence analysis of the FGFR2 gene demonstrated a sequence change, c.866A>C, in exon 7 that results in an amino acid change, p.Gln289Pro. This sequence change is absent from population databases (ExAc and GnomAD) and it has been reported in multiple patients with craniosynostosis syndromes including Crouzon syndrome (PMIDs: 7655462, 22355256, 11781872), Pfeiffer syndrome (PMID: 19066959), Jackson-Weiss syndrome (PMID: 7581378) and Saethre-Chotzen Syndrome (PMID: 16526917). The p.Gln289Pro change affects a moderately conserved amino acid residue located in a domain of the FGFR2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln289Pro substitution. The p.Gln289Pro amino acid change occurs in a region of the FGFR2 gene where other missense sequence changes have been described in patients with FGFR2-related disorders. These collective evidences indicate that this sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. - |
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 289 of the FGFR2 protein (p.Gln289Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGFR2-related craniosynostosis syndromes, including Crouzon syndrome, and type 1 Pfeiffer syndrome (PMID: 7655462, 16418739, 19066959). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13276). 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) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Crouzon syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Jackson-Weiss syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen
D;.;.;.;D;.;.;.;.;.;P;D;.;.
Vest4
MutPred
0.86
.;.;Gain of catalytic residue at W290 (P = 0.0489);.;.;Gain of catalytic residue at W290 (P = 0.0489);.;Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);.;Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);.;
MVP
MPC
1.8
ClinPred
D
GERP RS
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