5-132861635-T-C

Variant names:

• chr5-132861635-T-C
• rs976692105
• NM_005260.7:c.1319A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_005260.7(GDF9):​c.1319A>G​(p.Tyr440Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,611,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GDF9 NM_005260.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

GDF9 (HGNC:4224): (growth differentiation factor 9) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates ovarian function. Reduced expression of this gene may be associated with polycystic ovary syndrome and mutations in this gene may be more common in mothers of dizygotic twins. [provided by RefSeq, Jul 2016]

GDF9 Gene-Disease associations (from GenCC):

• premature ovarian failure 14

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005260.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF9	NM_005260.7	MANE Select	c.1319A>G	p.Tyr440Cys	missense	Exon 2 of 2	NP_005251.1	O60383
	GDF9	NM_001288824.4		c.1055A>G	p.Tyr352Cys	missense	Exon 3 of 3	NP_001275753.1	B4DXG3
	GDF9	NM_001288825.4		c.1055A>G	p.Tyr352Cys	missense	Exon 4 of 4	NP_001275754.1	B4DXG3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF9	ENST00000687138.1	MANE Select	c.1319A>G	p.Tyr440Cys	missense	Exon 2 of 2	ENSP00000510441.1	O60383
	GDF9	ENST00000378673.2	TSL:5	c.1319A>G	p.Tyr440Cys	missense	Exon 3 of 3	ENSP00000367942.2	O60383
	GDF9	ENST00000464378.2	TSL:2	c.1319A>G	p.Tyr440Cys	missense	Exon 3 of 3	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459554 Hom.: 0 Cov.: 28 AF XY: 0.00000826 AC XY: 6 AN XY: 726316

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109856

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.80
Mutation Taster		=49/51	disease causing

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: rs976692105; hg19: chr5-132197327;