rs121918501

Positions:

• chr10-121520050-A-C
• chr10-121520050-A-G
• chr10-121520050-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000141.5(FGFR2):​c.868T>G​(p.Trp290Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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. 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. W290C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.32

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]

FGFR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a strand (size 6) in uniprot entity FGFR2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr10-121520048-C-G is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-121520050-A-C is Pathogenic according to our data. Variant chr10-121520050-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13284.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-121520050-A-C is described in Lovd as [Pathogenic]. Variant chr10-121520050-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.868T>G	p.Trp290Gly	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.868T>G	p.Trp290Gly	missense_variant	7/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.868T>G	p.Trp290Gly	missense_variant	7/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.868T>G	p.Trp290Gly	missense_variant	6/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.868T>G	p.Trp290Gly	missense_variant	7/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.601T>G	p.Trp201Gly	missense_variant	6/17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.523T>G	p.Trp175Gly	missense_variant	5/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.601T>G	p.Trp201Gly	missense_variant	6/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.184T>G	p.Trp62Gly	missense_variant	6/17	1		ENSP00000474011.1
FGFR2	ENST00000369061.8	c.749-4731T>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.523T>G		non_coding_transcript_exon_variant	5/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Crouzon syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1995	- -

FGFR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The FGFR2 c.868T>G variant is predicted to result in the amino acid substitution p.Trp290Gly. This variant has been reported in individuals with Crouzon or Pfeiffer sydrome (Park et al. 1995. PubMed ID: 8528214; Wenger et al. 2017. PubMed ID: 27228464; Machado et al. 2017. PubMed ID: 28815901; Bukowska-Olech et al. 2022. PubMed ID: 35591945; Lajeunie et al. 2006. PubMed ID: 16418739). Alternate missense substitutions at the same amino acid position (p.Trp290Cys, p.Trp290Arg, p.Trp290Ser, and p.Trp290Leu) have also been reported in individuals affected with craniosynostosis, Pfeiffer or Crouzon syndrome (Wenger et al. 2017. PubMed ID: 27228464; Nazzaro et al. 2004. PubMed ID: 15565658, Oldridge et al. 1995. PubMed ID: 7655462; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). The c.868T>G (p.Trp290Gly) variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;D;.;D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;H;.;H;.;H;H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.86	P;.;.;.;B;.;.;.;.;.;D;D;.;.
Vest4		0.96
MutPred		0.99		.;.;Gain of disorder (P = 0.005);.;.;Gain of disorder (P = 0.005);.;Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);.;Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.99

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: rs121918501; hg19: chr10-123279564;