rs121918322

Variant names:

• chr13-21681060-G-A
• rs121918322
• NM_002010.3:c.296G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002010.3(FGF9):​c.296G>A​(p.Ser99Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGF9 NM_002010.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 16 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 13-21681060-G-A is Pathogenic according to our data. Variant chr13-21681060-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8705.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF9	NM_002010.3	c.296G>A	p.Ser99Asn	missense_variant	Exon 2 of 3	ENST00000382353.6	NP_002001.1
FGF9	XM_011534996.3	c.146G>A	p.Ser49Asn	missense_variant	Exon 2 of 3		XP_011533298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF9	ENST00000382353.6	c.296G>A	p.Ser99Asn	missense_variant	Exon 2 of 3	1	NM_002010.3	ENSP00000371790.5
FGF9	ENST00000461657.1	n.230G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5
FGF9	ENST00000478546.1	n.-53G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple synostoses syndrome 3 Pathogenic:1

Jul 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.024	D
Polyphen		0.44	B
Vest4		0.95
MutPred		0.75		Gain of catalytic residue at I100 (P = 5e-04);
MVP		0.89
MPC		1.7
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.94
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs121918322; hg19: chr13-22255199;