rs1219642

Positions:

• chr10-121588875-T-C

Variant summary

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

The NM_000141.5(FGFR2):​c.109+4834A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,878 control chromosomes in the GnomAD database, including 12,681 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 0.41 (12681 hom., cov: 31)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.109+4834A>G		intron_variant		ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.109+4834A>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.109+4834A>G		intron_variant		1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.109+4834A>G		intron_variant		1	NM_022970.4	ENSP00000410294	P4

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62014 AN: 151762 Hom.: 12673 Cov.: 31

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.409

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

GnomAD4 genome AF: 0.409 AC: 62044 AN: 151878 Hom.: 12681 Cov.: 31 AF XY: 0.411 AC XY: 30529 AN XY: 74232

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.405

Alfa AF: 0.396 Hom.: 3661

Bravo AF: 0.408

Asia WGS AF: 0.372 AC: 1294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.065
DANN	Benign	0.44

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: rs1219642; hg19: chr10-123348389;