13-21689811-T-C

Variant names:

• chr13-21689811-T-C
• rs6490667
• NM_002010.3:c.381+8666T>C

Variant summary

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

The NM_002010.3(FGF9):​c.381+8666T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,142 control chromosomes in the GnomAD database, including 7,144 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 0.28 (7144 hom., cov: 32)
• Consequence: FGF9 NM_002010.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.564
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF9	NM_002010.3	c.381+8666T>C		intron_variant	Intron 2 of 2	ENST00000382353.6	NP_002001.1
FGF9	XM_011534996.3	c.231+8666T>C		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.381+8666T>C		intron_variant	Intron 2 of 2	1	NM_002010.3	ENSP00000371790.5
FGF9	ENST00000461657.1	n.315+8666T>C		intron_variant	Intron 2 of 2	5
FGF9	ENST00000478546.1	n.141+8558T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42263 AN: 152022 Hom.: 7148 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.278 AC: 42269 AN: 152142 Hom.: 7144 Cov.: 32 AF XY: 0.282 AC XY: 20989 AN XY: 74376

African (AFR) AF: 0.0787 AC: 3267 AN: 41524

American (AMR) AF: 0.334 AC: 5110 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3470

East Asian (EAS) AF: 0.424 AC: 2186 AN: 5160

South Asian (SAS) AF: 0.344 AC: 1653 AN: 4812

European-Finnish (FIN) AF: 0.404 AC: 4281 AN: 10592

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23555 AN: 67982

Other (OTH) AF: 0.291 AC: 614 AN: 2112

Alfa AF: 0.315 Hom.: 2778

Bravo AF: 0.263

Asia WGS AF: 0.370 AC: 1285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.0
DANN	Benign	0.77
PhyloP100		0.56
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: rs6490667; hg19: chr13-22263950;