10-121520008-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000141.5(FGFR2):c.910G>A(p.Asp304Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D304D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR2_HUMAN there are 114 pathogenic changes around while only 5 benign (96%) in NM_000141.5

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.910G>A	p.Asp304Asn	missense_variant	Exon 7 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.910G>A	p.Asp304Asn	missense_variant	Exon 7 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.910G>A	p.Asp304Asn	missense_variant	Exon 7 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.910G>A	p.Asp304Asn	missense_variant	Exon 6 of 17	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.910G>A	p.Asp304Asn	missense_variant	Exon 7 of 17	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000613048.4 link	c.643G>A	p.Asp215Asn	missense_variant	Exon 6 of 17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369059.5 link	c.565G>A	p.Asp189Asn	missense_variant	Exon 5 of 16	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.643G>A	p.Asp215Asn	missense_variant	Exon 6 of 17	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000478859.5 link	c.226G>A	p.Asp76Asn	missense_variant	Exon 6 of 17	1		ENSP00000474011.1	S4R381
FGFR2	ENST00000369061.8 link	c.749-4689G>A		intron_variant	Intron 5 of 14	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000604236.5 link	n.565G>A		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251458

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FGFR2-related craniosynostosis

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 304 of the FGFR2 protein (p.Asp304Asn). This variant is present in population databases (rs370877537, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FGFR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 566306). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;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

Uncertain:1

Dec 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Benign

0.050

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.54

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

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.94

.;.;L;.;.;L;.;L;.;L;.;L;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.1

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

REVEL

Uncertain

0.51

Sift

Benign

0.079

T;.;T;.;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.57

P;.;.;.;B;.;.;.;.;.;B;P;.;.

Vest4

0.46

MVP

0.78

MPC

1.3

ClinPred

0.91

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.80

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