rs3135730

Positions:

• chr10-121566280-T-C
• chr10-121566280-T-G

Variant summary

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

The NM_000141.5(FGFR2):​c.110-576A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,112 control chromosomes in the GnomAD database, including 3,656 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 0.17 (3656 hom., cov: 32)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.110-576A>G		intron_variant		ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.110-576A>G		intron_variant		ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.110-576A>G		intron_variant		1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.110-576A>G		intron_variant		1	NM_022970.4	ENSP00000410294	P4

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26263 AN: 151994 Hom.: 3642 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0796

Gnomad EAS AF: 0.0764

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.173 AC: 26317 AN: 152112 Hom.: 3656 Cov.: 32 AF XY: 0.170 AC XY: 12649 AN XY: 74366

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.0796

Gnomad4 EAS AF: 0.0758

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0822

Gnomad4 OTH AF: 0.153

Alfa AF: 0.0992 Hom.: 1611

Bravo AF: 0.188

Asia WGS AF: 0.0650 AC: 229 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	1.1
DANN	Benign	0.73

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: rs3135730; hg19: chr10-123325794;