rs10491279

Variant names:

• chr5-132862408-C-T
• rs10491279
• NM_005260.7:c.546G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_005260.7(GDF9):​c.546G>A​(p.Glu182Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,476 control chromosomes in the GnomAD database, including 22,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2267 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20587 hom.)
• Consequence: GDF9 NM_005260.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.696
• Publications: 29 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-132862408-C-T is Benign according to our data. Variant chr5-132862408-C-T is described in ClinVar as Benign. ClinVar VariationId is 137459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.696 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 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.546G>A	p.Glu182Glu	synonymous	Exon 2 of 2	NP_005251.1	O60383
	GDF9	NM_001288824.4		c.282G>A	p.Glu94Glu	synonymous	Exon 3 of 3	NP_001275753.1	B4DXG3
	GDF9	NM_001288825.4		c.282G>A	p.Glu94Glu	synonymous	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.546G>A	p.Glu182Glu	synonymous	Exon 2 of 2	ENSP00000510441.1	O60383
	GDF9	ENST00000378673.2	TSL:5	c.546G>A	p.Glu182Glu	synonymous	Exon 3 of 3	ENSP00000367942.2	O60383
	GDF9	ENST00000464378.2	TSL:2	c.546G>A	p.Glu182Glu	synonymous	Exon 3 of 3	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25813 AN: 152000 Hom.: 2265 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0574

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.141 AC: 35566 AN: 251406 AF XY: 0.138

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.164 AC: 239916 AN: 1461358 Hom.: 20587 Cov.: 32 AF XY: 0.162 AC XY: 117837 AN XY: 726994

African (AFR) AF: 0.205 AC: 6867 AN: 33464

American (AMR) AF: 0.0935 AC: 4182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4211 AN: 26126

East Asian (EAS) AF: 0.138 AC: 5474 AN: 39696

South Asian (SAS) AF: 0.0645 AC: 5567 AN: 86256

European-Finnish (FIN) AF: 0.151 AC: 8048 AN: 53400

Middle Eastern (MID) AF: 0.136 AC: 784 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194720 AN: 1111554

Other (OTH) AF: 0.167 AC: 10063 AN: 60370

GnomAD4 genome AF: 0.170 AC: 25829 AN: 152118 Hom.: 2267 Cov.: 32 AF XY: 0.166 AC XY: 12327 AN XY: 74346

African (AFR) AF: 0.203 AC: 8438 AN: 41482

American (AMR) AF: 0.132 AC: 2018 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 525 AN: 3470

East Asian (EAS) AF: 0.145 AC: 749 AN: 5174

South Asian (SAS) AF: 0.0577 AC: 278 AN: 4820

European-Finnish (FIN) AF: 0.154 AC: 1625 AN: 10570

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11658 AN: 67988

Other (OTH) AF: 0.178 AC: 375 AN: 2112

Alfa AF: 0.170 Hom.: 1515

Bravo AF: 0.171

Asia WGS AF: 0.0990 AC: 346 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.168

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	GDF9-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.49
DANN	Benign	0.50
PhyloP100		-0.70
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: rs10491279; hg19: chr5-132198100; COSMIC: COSV51526492; COSMIC: COSV51526492;