10-121520095-C-G

Position:

chr10-121520095-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_000141.5(FGFR2):c.823G>C(p.Glu275Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

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 4 ACMG points.

PM1

In a strand (size 3) in uniprot entity FGFR2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000141.5

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.35259572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_022970.4 linkuse as main transcript	c.823G>C	p.Glu275Gln	missense_variant	7/18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5 linkuse as main transcript	c.823G>C	p.Glu275Gln	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7 linkuse as main transcript	c.823G>C	p.Glu275Gln	missense_variant	7/18	1	NM_022970.4	ENSP00000410294	P4	P21802-3
FGFR2	ENST00000358487.10 linkuse as main transcript	c.823G>C	p.Glu275Gln	missense_variant	7/18	1	NM_000141.5	ENSP00000351276	A2	P21802-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135886

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:

1461878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

FGFR2-related craniosynostosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 478047). This variant has not been reported in the literature in individuals affected with FGFR2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 275 of the FGFR2 protein (p.Glu275Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

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

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.35

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.81

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

N;.;N;.;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.054

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

Sift4G

Benign

0.26

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

Polyphen

0.094

B;.;.;.;B;.;.;.;.;.;B;B;.;.

Vest4

0.28

MutPred

0.49

.;.;Loss of sheet (P = 0.1398);.;.;Loss of sheet (P = 0.1398);.;Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;

MVP

0.73

MPC

0.77

ClinPred

0.47

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.86

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