rs3135802

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000141.5(FGFR2):c.1864-17T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,612,798 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 33)

Exomes 𝑓: 0.023 ( 434 hom. )

Consequence

FGFR2
NM_000141.5 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.345

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 10-121488130-A-C is Benign according to our data. Variant chr10-121488130-A-C is described in ClinVar as [Benign]. Clinvar id is 255315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121488130-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3123/151502) while in subpopulation NFE AF= 0.0254 (1722/67908). AF 95% confidence interval is 0.0244. There are 50 homozygotes in gnomad4. There are 1511 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5 linkuse as main transcript	c.1864-17T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358487.10
FGFR2	NM_022970.4 linkuse as main transcript	c.1867-17T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10 linkuse as main transcript	c.1864-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000141.5	A2	P21802-1
FGFR2	ENST00000457416.7 linkuse as main transcript	c.1867-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_022970.4	P4	P21802-3

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3124

AN:

151384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0210

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0212

GnomAD3 exomes

AF:

0.0191

AC:

4797

AN:

250920

Hom.:

AF XY:

0.0191

AC XY:

2588

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0152

Gnomad SAS exome

AF:

0.00519

Gnomad FIN exome

AF:

0.0344

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0243

GnomAD4 exome

AF:

0.0226

AC:

32986

AN:

1461296

Hom.:

434

Cov.:

AF XY:

0.0219

AC XY:

15948

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.0169

Gnomad4 AMR exome

AF:

0.0125

Gnomad4 ASJ exome

AF:

0.0166

Gnomad4 EAS exome

AF:

0.00781

Gnomad4 SAS exome

AF:

0.00601

Gnomad4 FIN exome

AF:

0.0349

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0206

AC:

3123

AN:

151502

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1511

AN XY:

74048

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.0163

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.00581

Gnomad4 FIN

AF:

0.0322

Gnomad4 NFE

AF:

0.0254

Gnomad4 OTH

AF:

0.0210

Alfa

AF:

0.0208

Hom.:

Bravo

AF:

0.0191

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

FGFR2-related craniosynostosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.2

DANN

Benign

0.61

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