10-121593801-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000141.5(FGFR2):c.17G>A(p.Arg6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6P) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.57

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 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.16094524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 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.17G>A	p.Arg6His	missense_variant	Exon 2 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.17G>A	p.Arg6His	missense_variant	Exon 1 of 17	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 of 17	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000613048.4 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 of 17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369061.8 link	c.17G>A	p.Arg6His	missense_variant	Exon 1 of 15	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000369059.5 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 of 16	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.17G>A	p.Arg6His	missense_variant	Exon 2 of 17	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000604236.5 link	n.17G>A		non_coding_transcript_exon_variant	Exon 2 of 17	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251426

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135904

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

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:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR2: PM2, BP4 -

Oct 18, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27072194) -

FGFR2-related craniosynostosis

Uncertain:1

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 6 of the FGFR2 protein (p.Arg6His). This variant is present in population databases (rs3750819, gnomAD 0.0009%). 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: 1316348). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

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

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.063

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.55

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

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.58

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

REVEL

Benign

0.25

Sift

Benign

0.23

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

Sift4G

Benign

0.54

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

Polyphen

0.72, 0.32, 0.036, 0.81, 0.76

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

Vest4

0.23

MutPred

0.49

Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);

MVP

0.62

MPC

0.27

ClinPred

0.15

GERP RS

4.3

Varity_R

0.035

gMVP

0.32

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