chr10-121515280-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_022970.4(FGFR2):c.1127A>G(p.Tyr376Cys) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y376F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

FGFR2
NM_022970.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.94

Publications

123 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 17 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr10-121515280-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3075688.

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, 0.931

PP5

Variant 10-121515280-T-C is Pathogenic according to our data. Variant chr10-121515280-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13277.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.1127A>G	p.Tyr376Cys	missense_variant	Exon 9 of 18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5 link	c.1124A>G	p.Tyr375Cys	missense_variant	Exon 9 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR2	ENST00000457416.7 link	c.1127A>G	p.Tyr376Cys	missense_variant	Exon 9 of 18	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000358487.10 link	c.1124A>G	p.Tyr375Cys	missense_variant	Exon 9 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000369056.5 link	c.1127A>G	p.Tyr376Cys	missense_variant	Exon 8 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7 link	c.1127A>G	p.Tyr376Cys	missense_variant	Exon 9 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4 link	c.857A>G	p.Tyr286Cys	missense_variant	Exon 8 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8 link	c.788A>G	p.Tyr263Cys	missense_variant	Exon 6 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5 link	c.782A>G	p.Tyr261Cys	missense_variant	Exon 7 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7 link	c.860A>G	p.Tyr287Cys	missense_variant	Exon 8 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5 link	c.440A>G	p.Tyr147Cys	missense_variant	Exon 8 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5 link	n.*171A>G		non_coding_transcript_exon_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5 link	n.*171A>G		3_prime_UTR_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000429361.5 link	c.-101A>G		upstream_gene_variant		5		ENSP00000404219.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Beare-Stevenson cutis gyrata syndrome

Pathogenic:5

Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Recurrent pathogenic: RCV000762799 -

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

- -

Jan 09, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Medical Genetics, Oslo University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:3

Mar 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12000365, 12900900, 23754559, 16531735, 25937001, 17525745, 19610084, 12145519, 27079505, 21397175, 17449949, 35050789, 32158469, 21479481, 8696350, 9545103, 25706251, 20856019) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FGFR2-related craniosynostosis

Pathogenic:1

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the FGFR2 protein (p.Tyr375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Beare-Stevenson cutis gyrata syndrome (PMID: 8696350, 12145519, 12900900, 16531735, 20856019, 21397175, 25706251, 25937001, 27079505). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13277). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGFR2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

FGFR2-related disorder

Pathogenic:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FGFR2 c.1124A>G variant is predicted to result in the amino acid substitution p.Tyr375Cys. This variant has been well documented to be pathogenic for Beare-Stevenson cutis gyrata syndrome (see for example Przylepa et al. 1996. PubMed ID: 8696350; Fonseca et al. 2008. PubMed ID: 21479481; Wenger et al. 2015. PMID: 25706251; Ron et al. 2016. PubMed ID: 27079505). This variant has also been identified as a de novo variant in an infant with a clinical diagnosis of Pfeiffer syndrome (Willig et al. 2015. PubMed ID: 25937001). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0038356:Neoplasm of stomach;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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Endometrial carcinoma

Pathogenic:1

Nov 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;.;.;D;.;.;T;.;T;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

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

0.29

MetaRNN

Pathogenic

0.93

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

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

2.9

.;.;.;M;.;.;.;M;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

D;D;.;D;.;D;D;D;.;D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D;.;D;.;D;D;D;.;D;D;D;D;D

Sift4G

Uncertain

0.0070

D;T;T;D;T;D;T;D;D;D;D;D;D;.

Polyphen

1.0, 1.0, 0.93

.;D;.;D;.;D;.;.;.;.;P;D;.;.

Vest4

0.93

MutPred

0.81

.;.;.;Loss of disorder (P = 0.1004);.;.;.;Loss of disorder (P = 0.1004);.;.;.;.;.;.;

MVP

0.92

MPC

2.0

ClinPred

0.99

GERP RS

5.8

PromoterAI

0.069

Neutral

(source)

Varity_R

0.71

gMVP

0.92

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