rs1057519799

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000141.5(FGFR2):c.1611G>T(p.Met537Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.1611G>T	p.Met537Ile	missense_variant	Exon 12 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.1611G>T	p.Met537Ile	missense_variant	Exon 12 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.1614G>T	p.Met538Ile	missense_variant	Exon 12 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.1614G>T	p.Met538Ile	missense_variant	Exon 11 of 17	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.1614G>T	p.Met538Ile	missense_variant	Exon 12 of 17	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000613048.4 link	c.1344G>T	p.Met448Ile	missense_variant	Exon 11 of 17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369061.8 link	c.1275G>T	p.Met425Ile	missense_variant	Exon 9 of 15	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000369059.5 link	c.1269G>T	p.Met423Ile	missense_variant	Exon 10 of 16	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.1347G>T	p.Met449Ile	missense_variant	Exon 11 of 17	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000478859.5 link	c.927G>T	p.Met309Ile	missense_variant	Exon 11 of 17	1		ENSP00000474011.1	S4R381
FGFR2	ENST00000429361.5 link	c.387G>T	p.Met129Ile	missense_variant	Exon 4 of 9	5		ENSP00000404219.1	H7C265
FGFR2	ENST00000604236.5 link	n.*658G>T		non_coding_transcript_exon_variant	Exon 11 of 17	1		ENSP00000474109.1	S4R3B2
FGFR2	ENST00000604236.5 link	n.*658G>T		3_prime_UTR_variant	Exon 11 of 17	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727214

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation

Pathogenic:1

Dec 26, 2014

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.69

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

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

-0.79

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

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.9

D;D;.;D;.;D;N;D;D;D;.;D;D;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.036

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

Polyphen

0.92, 0.99, 1.0, 0.43, 0.99

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

Vest4

0.62

MutPred

0.43

.;.;.;Loss of disorder (P = 0.0556);.;.;.;.;.;.;Loss of disorder (P = 0.0556);.;.;.;.;.;

MVP

0.91

MPC

1.9

ClinPred

0.99

GERP RS

5.2

Varity_R

0.93

gMVP

0.85

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