rs3135753

Positions:

• chr10-121521144-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000141.5(FGFR2):​c.749-975A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 152,354 control chromosomes in the GnomAD database, including 2 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 0.0040 (2 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.146

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=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00397 (605/152354) while in subpopulation NFE AF= 0.00476 (324/68028). AF 95% confidence interval is 0.00434. There are 2 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.749-975A>G		intron_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.749-975A>G		intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.749-975A>G		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.749-975A>G		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.749-975A>G		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.482-975A>G		intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.749-5825A>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.404-975A>G		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.482-975A>G		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.65-975A>G		intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.404-975A>G		intron_variant		1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 605 AN: 152236 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00334

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

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152354 Hom.: 2 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74506

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.00476

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00467 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3135753; hg19: chr10-123280658;