rs121918501

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_022970.4(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. 13/22 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_022970.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 9.32

Publications

42 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Apert syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
Beare-Stevenson cutis gyrata syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
Crouzon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
Jackson-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
LADD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
bent bone dysplasia syndrome 1
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
familial scaphocephaly syndrome, McGillivray type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Saethre-Chotzen syndrome
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
Antley-Bixler syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_022970.4

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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.

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 VariationId is 13284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_022970.4 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 7 of 18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 7 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR2	ENST00000457416.7 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 7 of 18	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000358487.10 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 7 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000369056.5 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 6 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7 link	c.868T>G	p.Trp290Gly	missense_variant	Exon 7 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4 link	c.601T>G	p.Trp201Gly	missense_variant	Exon 6 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5 link	c.523T>G	p.Trp175Gly	missense_variant	Exon 5 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7 link	c.601T>G	p.Trp201Gly	missense_variant	Exon 6 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5 link	c.184T>G	p.Trp62Gly	missense_variant	Exon 6 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5 link	n.523T>G		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1
FGFR2	ENST00000369061.8 link	c.749-4731T>G		intron_variant	Intron 5 of 14	1		ENSP00000358057.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Crouzon syndrome

Pathogenic:2

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

FGFR2-related disorder

Pathogenic:1

Sep 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

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

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.4

.;.;H;.;.;H;.;H;.;H;.;H;H;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.89

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

GERP RS

5.8

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over