rs4705974

Variant names:

• chr5-132863250-C-T
• rs4705974
• NM_005260.7:c.398-694G>A

Variant summary

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

The NM_005260.7(GDF9):​c.398-694G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,114 control chromosomes in the GnomAD database, including 2,538 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 0.17 (2538 hom., cov: 32)
• Consequence: GDF9 NM_005260.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

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.398-694G>A		intron	N/A	NP_005251.1	O60383
	GDF9	NM_001288824.4		c.134-694G>A		intron	N/A	NP_001275753.1	B4DXG3
	GDF9	NM_001288825.4		c.134-694G>A		intron	N/A	NP_001275754.1	B4DXG3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF9	ENST00000687138.1	MANE Select	c.398-694G>A		intron	N/A	ENSP00000510441.1	O60383
	GDF9	ENST00000378673.2	TSL:5	c.398-694G>A		intron	N/A	ENSP00000367942.2	O60383
	GDF9	ENST00000464378.2	TSL:2	c.398-694G>A		intron	N/A	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25937 AN: 151996 Hom.: 2536 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.171 AC: 25964 AN: 152114 Hom.: 2538 Cov.: 32 AF XY: 0.168 AC XY: 12512 AN XY: 74362

African (AFR) AF: 0.266 AC: 11044 AN: 41462

American (AMR) AF: 0.104 AC: 1593 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3468

East Asian (EAS) AF: 0.117 AC: 609 AN: 5186

South Asian (SAS) AF: 0.196 AC: 946 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1205 AN: 10584

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9643 AN: 67978

Other (OTH) AF: 0.161 AC: 341 AN: 2112

Alfa AF: 0.162 Hom.: 293

Bravo AF: 0.172

Asia WGS AF: 0.143 AC: 501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4705974; hg19: chr5-132198942;