rs387906678

Positions:

• chr10-121515263-A-C
• chr10-121515263-A-G
• chr10-121515263-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1141T>G​(p.Tyr381Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. Y381C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.23

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]

ACMG classification

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 1 benign, 4 uncertain in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121515262-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423481.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, FGFR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 10-121515263-A-C is Pathogenic according to our data. Variant chr10-121515263-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 29856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121515263-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.1144T>G	p.Tyr382Asp	missense_variant	9/18	ENST00000457416.7
FGFR2	NM_000141.5	c.1141T>G	p.Tyr381Asp	missense_variant	9/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.1144T>G	p.Tyr382Asp	missense_variant	9/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.1141T>G	p.Tyr381Asp	missense_variant	9/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bent bone dysplasia syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are known mechanisms of disease in this gene. Variants which are involved in LADD syndrome (MIM#149730) and bent bone dysplasia syndrome (MIM#614592), generally in the tyrosine kinase domain and hydrophobic transmembrane domain, respectively, exert a LoF effect. Variants involved in craniosynostosis (MIM#207410, 101200, 123790, 101600, 123500, 123150) are located within the extracellular ligand binding domain and exert a GoF effect (PMID: 27240702). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity in Crouzon syndrome (MIM#123500; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the transmembrane domain (DECIPHER, PMID: 27240702). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in bent bone dysplasia syndrome (MIM#614592) and has been reported in at least ten individuals, with some confirmed de novo (PMID: 22387015, 26446305, 26573129, 27240702). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies suggest a damaging effect, specifically, an increased accumulation in the nucleolus resulting in a disruption of nucleolar structure and increased ribosomal biogenesis that likely contributes to altered osteoblast differentiation (Neben, C, et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24908667, 22387015, 25356970, 26573129, 26446305, 30620790, 29230096, 27240702, 28595297) -

FGFR2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2023

The FGFR2 c.1141T>G variant is predicted to result in the amino acid substitution p.Tyr381Asp. This variant has been reported in the de novo or heterozygous states in individuals with bent bone dysplasia (Merrill et al. 2012. PubMed ID: 22387015; Stichelbout et al. 2015. PubMed ID: 26573129; Krakow et al. 2016. PubMed ID: 27240702). This variant has also been reported in the heterozygous state in an individual with craniosynostosis syndrome (Farwell et al. 2014. PubMed ID: 25356970. Table S3). Additionally, functional studies showed that this variant could reduce FGF canonical signaling and enhance nucleolar occupancy of FGFR2 at the ribosomal DNA promoter, therefore increasing osteoprogenitors cell proliferation and decreasing osteoblast differentiation (Merrill et al. 2012. PubMed ID: 22387015; Neben et al. 2014. PubMed ID: 24908667). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2012

Please see table 3 in supplementary results of the main report. This variant has not been detected in conjunction with a pathogenic mutation to date. Allele frequency data in population-based cohorts is not currently available. This amino acid position is highly conserved in available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.996 (sensitivity: 0.36; specificity: 0.97)This alteration is predicted to be tolerated with a score of 0.120 (conservation: 2.04) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.4	D;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.;D;.;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.049	D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99, 1.0, 1.0, 0.89	.;D;.;D;.;D;.;.;.;.;P;D;.;.
Vest4		0.91
MutPred		0.58		.;.;.;Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;.;.;.;.;
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.91

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: rs387906678; hg19: chr10-123274777;