chr10-121565500-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_000141.5(FGFR2):c.314A>G(p.Tyr105Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.24

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.991

PP5

Variant 10-121565500-T-C is Pathogenic according to our data. Variant chr10-121565500-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121565500-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR2	ENST00000358487.10 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 2 of 17	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 3 of 17	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000369061.8 link	c.314A>G	p.Tyr105Cys	missense_variant	Exon 2 of 15	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000613048.4 link	c.110-921A>G		intron_variant	Intron 2 of 16	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369059.5 link	c.110-14041A>G		intron_variant	Intron 2 of 15	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.110-921A>G		intron_variant	Intron 2 of 16	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000604236.5 link	n.110-14041A>G		intron_variant	Intron 2 of 16	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251352

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a 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: 16418739, 25425289, 34169787, 8946174, 27928320, 11781872, 24127277, 23754559, 34538793) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Crouzon syndrome

Pathogenic:2

Jan 12, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5 -

Feb 02, 2022

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr105Cys variant is a recurrent pathogenic variant that has been reported in both the medical literature and patient databases among individuals with craniosynostosis and Crouzon syndrome (MIM #123500) (PMID: 8946174 and others). The p.Tyr105Cys variant replaces a tyrosine residue at amino acid position 105 with a cysteine in the immunoglobulin-like domain of the FGFR2 protein. This variant is present at an a very low frequency in a database of the general population (1 of 251,352 alleles, gnomAD v.2.1.1). Typically, FGFR2-related craniosynostosis variants are activating, although functional validation has not been performed to our knowledge for this variant. The FGFR2 p.Tyr105Cys variant has been found to be a de novo change in some individuals, and has also been demonstrated to segregate with the phenotype in families with multiple affected members (PMID: 16418739). -

FGFR2-related craniosynostosis

Pathogenic:1

Jul 15, 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 105 of the FGFR2 protein (p.Tyr105Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Crouzon syndrome (PMID: 1641873, 8946174, 11781872, 24127277; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314A>G (p.Y105C) alteration is located in exon 3 (coding exon 2) of the FGFR2 gene. This alteration results from an A to G substitution at nucleotide position 314, causing the tyrosine (Y) at amino acid position 105 to be replaced by a cysteine (C). for FGFR2-related craniosynostosis disorders; however, its clinical significance for FGFR2-related lacrimoauriculodentodigital syndrome is uncertain. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as heterozygous in individuals with features consistent with FGFR2-related craniosynostosis disorders or suspected to have Crouzon syndrome; in at least one individual, it was determined to be a de novo variant (Pulleyn, 1996; Kan, 2002; Lajeunie, 2006; Roscioli; 2013; Timberlake, 2023). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Bent bone dysplasia syndrome 1

Pathogenic:1

Aug 09, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PP3 -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

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

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.96

Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);Gain of catalytic residue at Y105 (P = 0.1171);

MVP

0.96

MPC

0.93

ClinPred

1.0

GERP RS

5.2

Varity_R

0.83

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over