13-21696649-A-G

Variant names:

• chr13-21696649-A-G
• rs12870202
• NM_002010.3:c.382-4541A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002010.3(FGF9):​c.382-4541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 152,106 control chromosomes in the GnomAD database, including 11,702 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 0.35 (11702 hom., cov: 32)
• Consequence: FGF9 NM_002010.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238
• Publications: 2 publications found

Genes affected

FGF9 (HGNC:3687): (fibroblast growth factor 9) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis. [provided by RefSeq, Jul 2008]

FGF9 Gene-Disease associations (from GenCC):

• multiple synostoses syndrome 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• multiple synostoses syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF9	NM_002010.3	c.382-4541A>G		intron_variant	Intron 2 of 2	ENST00000382353.6	NP_002001.1
FGF9	XM_011534996.3	c.232-4541A>G		intron_variant	Intron 2 of 2		XP_011533298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF9	ENST00000382353.6	c.382-4541A>G		intron_variant	Intron 2 of 2	1	NM_002010.3	ENSP00000371790.5
FGF9	ENST00000461657.1	n.316-4541A>G		intron_variant	Intron 2 of 2	5
FGF9	ENST00000478546.1	n.142-4541A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53751 AN: 151988 Hom.: 11688 Cov.: 32

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.353 AC: 53769 AN: 152106 Hom.: 11702 Cov.: 32 AF XY: 0.357 AC XY: 26525 AN XY: 74342

African (AFR) AF: 0.0898 AC: 3729 AN: 41530

American (AMR) AF: 0.467 AC: 7147 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1460 AN: 3470

East Asian (EAS) AF: 0.564 AC: 2918 AN: 5170

South Asian (SAS) AF: 0.551 AC: 2658 AN: 4828

European-Finnish (FIN) AF: 0.331 AC: 3493 AN: 10544

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30895 AN: 67960

Other (OTH) AF: 0.389 AC: 819 AN: 2108

Alfa AF: 0.306 Hom.: 3626

Bravo AF: 0.350

Asia WGS AF: 0.541 AC: 1878 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.80
DANN	Benign	0.60
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12870202; hg19: chr13-22270788; COSMIC: COSV66644878;