10-121485320-C-T

Position:

• chr10-121485320-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):​c.2195+75G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,598,834 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (774 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1938 hom.)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.854

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-121485320-C-T is Benign according to our data. Variant chr10-121485320-C-T is described in ClinVar as [Benign]. Clinvar id is 1222606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2195+75G>A		intron_variant		ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.2198+75G>A		intron_variant		ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.2195+75G>A		intron_variant		1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.2198+75G>A		intron_variant		1	NM_022970.4	ENSP00000410294	P4

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12020 AN: 152010 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0456 AC: 65939 AN: 1446706 Hom.: 1938 AF XY: 0.0444 AC XY: 31991 AN XY: 720536

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.00916

Gnomad4 SAS exome AF: 0.0177

Gnomad4 FIN exome AF: 0.0634

Gnomad4 NFE exome AF: 0.0438

Gnomad4 OTH exome AF: 0.0525

GnomAD4 genome AF: 0.0792 AC: 12050 AN: 152128 Hom.: 774 Cov.: 32 AF XY: 0.0776 AC XY: 5773 AN XY: 74374

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0384

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0608

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0595

Alfa AF: 0.0436 Hom.: 275

Bravo AF: 0.0823

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.71
DANN	Benign	0.47

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: rs1613776; hg19: chr10-123244834;