rs121918504
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong
The NM_000141.5(FGFR2):c.943G>T(p.Ala315Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
FGFR2
NM_000141.5 missense
NM_000141.5 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 7.85
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 13 ACMG points.
PM1
In a disulfide_bond (size 64) in uniprot entity FGFR2_HUMAN there are 35 pathogenic changes around while only 1 benign (97%) in NM_000141.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
PP5
Variant 10-121517460-C-A is Pathogenic according to our data. Variant chr10-121517460-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517460-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGFR2 | NM_000141.5 | c.943G>T | p.Ala315Ser | missense_variant | 8/18 | ENST00000358487.10 | NP_000132.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000358487.10 | c.943G>T | p.Ala315Ser | missense_variant | 8/18 | 1 | NM_000141.5 | ENSP00000351276.6 | ||
FGFR2 | ENST00000613048.4 | c.676G>T | p.Ala226Ser | missense_variant | 7/17 | 5 | ENSP00000484154.1 | |||
FGFR2 | ENST00000478859.5 | c.259G>T | p.Ala87Ser | missense_variant | 7/17 | 1 | ENSP00000474011.1 | |||
FGFR2 | ENST00000457416.7 | c.1087+1222G>T | intron_variant | 1 | ENSP00000410294.2 | |||||
FGFR2 | ENST00000369056.5 | c.1087+1222G>T | intron_variant | 1 | ENSP00000358052.1 | |||||
FGFR2 | ENST00000369058.7 | c.1087+1222G>T | intron_variant | 1 | ENSP00000358054.3 | |||||
FGFR2 | ENST00000369061.8 | c.749-2141G>T | intron_variant | 1 | ENSP00000358057.4 | |||||
FGFR2 | ENST00000369059.5 | c.742+1222G>T | intron_variant | 5 | ENSP00000358055.1 | |||||
FGFR2 | ENST00000360144.7 | c.820+1222G>T | intron_variant | 2 | ENSP00000353262.3 | |||||
FGFR2 | ENST00000604236.5 | n.746G>T | non_coding_transcript_exon_variant | 7/17 | 1 | ENSP00000474109.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727228
GnomAD4 exome
AF:
AC:
10
AN:
1461862
Hom.:
Cov.:
31
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AC XY:
5
AN XY:
727228
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 15, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
FGFR2-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 04, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13289). This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 10951518, 12357470, 24127277, 28611549). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the FGFR2 protein (p.Ala315Ser). - |
Craniosynostosis, nonsyndromic unicoronal Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2000 | - - |
Crouzon syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 18, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;T;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;N;.;.;N;.;.
PROVEAN
Benign
N;.;N;.;N;N;.;N
REVEL
Benign
Sift
Benign
T;.;T;.;T;T;.;T
Sift4G
Benign
T;T;T;T;T;T;T;.
Polyphen
B;.;.;.;B;.;.;.
Vest4
MutPred
0.61
.;.;Gain of glycosylation at A315 (P = 0.0242);.;.;Gain of glycosylation at A315 (P = 0.0242);.;.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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