rs1219648

chr10-121586676-A-Gchr10-121586676-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000141.5(FGFR2):c.109+7033T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,050 control chromosomes in the GnomAD database, including 12,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.41 (12688 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.442

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-121586676-A-G is Benign according to our data. Variant chr10-121586676-A-G is described in ClinVar as [Benign]. Clinvar id is 1663397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.109+7033T>C		intron_variant		ENST00000358487.10
FGFR2	NM_022970.4	c.109+7033T>C		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.109+7033T>C		intron_variant		1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.109+7033T>C		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.408 AC: 62043 AN: 151932 Hom.: 12679 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.408 AC: 62074 AN: 152050 Hom.: 12688 Cov.: 33 AF XY: 0.411 AC XY: 30552 AN XY: 74344

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.403

Alfa AF: 0.396 Hom.: 22831

Bravo AF: 0.408

Asia WGS AF: 0.372 AC: 1294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.19
Dann	Benign	0.74

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: rs1219648; hg19: chr10-123346190;