rs4752566

Positions:

• chr10-121508117-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000141.5(FGFR2):​c.1288-4176C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,086 control chromosomes in the GnomAD database, including 13,780 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (13780 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1288-4176C>A		intron_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1288-4176C>A		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1291-4176C>A		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1291-4176C>A		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1291-4176C>A		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1021-4176C>A		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.952-4176C>A		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.946-4176C>A		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1024-4176C>A		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.604-4176C>A		intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.64-4176C>A		intron_variant		5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*335-4176C>A		intron_variant		1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59234 AN: 151968 Hom.: 13787 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.418

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.389 AC: 59230 AN: 152086 Hom.: 13780 Cov.: 33 AF XY: 0.398 AC XY: 29608 AN XY: 74330

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.559

Gnomad4 EAS AF: 0.885

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.486

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.419

Alfa AF: 0.445 Hom.: 22069

Bravo AF: 0.374

Asia WGS AF: 0.684 AC: 2377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs4752566; hg19: chr10-123267631;