rs3135736

chr10-121553500-A-C

Variant summary

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

The NM_000141.5(FGFR2):c.455-2041T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 152,208 control chromosomes in the GnomAD database, including 1,643 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 0.091 (1643 hom., cov: 32)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0830

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.455-2041T>G		intron_variant		ENST00000358487.10
FGFR2	NM_022970.4	c.455-2041T>G		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.455-2041T>G		intron_variant		1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.455-2041T>G		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.0906 AC: 13772 AN: 152090 Hom.: 1626 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0853

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.0726

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

GnomAD4 genome AF: 0.0909 AC: 13836 AN: 152208 Hom.: 1643 Cov.: 32 AF XY: 0.0903 AC XY: 6719 AN XY: 74436

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.0861

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.0720

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.0302

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.0723

Alfa AF: 0.0857 Hom.: 233

Bravo AF: 0.105

Asia WGS AF: 0.0550 AC: 193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	7.7
Dann	Benign	0.66

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: rs3135736; hg19: chr10-123313014;