dbSNP rs11748063: GDF9:c.-718G>A (chr5-132865251-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005260.7(GDF9):c.-718G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,204 control chromosomes in the GnomAD database, including 9,760 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 0.35 ( 9756 hom., cov: 32)

Exomes 𝑓: 0.22 ( 4 hom. )

Consequence

GDF9
NM_005260.7 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.152

Publications

10 publications found

Variant links:

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)

GDF9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF9	NM_005260.7 link	c.-718G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000687138.1	NP_005251.1	O60383
GDF9	NM_005260.7 link	c.-718G>A		5_prime_UTR_variant	Exon 1 of 2	ENST00000687138.1	NP_005251.1	O60383

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF9	ENST00000687138.1 link	c.-718G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2		NM_005260.7	ENSP00000510441.1		O60383
GDF9	ENST00000687138.1 link	c.-718G>A		5_prime_UTR_variant	Exon 1 of 2		NM_005260.7	ENSP00000510441.1		O60383

Frequencies

GnomAD3 genomes

AF:

0.348

AC:

52861

AN:

151924

Hom.:

9745

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.381

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.360

GnomAD4 exome

AF:

0.216

AC:

AN:

162

Hom.:

Cov.:

AF XY:

0.212

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.229

AC:

AN:

144

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.348

AC:

52910

AN:

152042

Hom.:

9756

Cov.:

AF XY:

0.342

AC XY:

25386

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.479

AC:

19841

AN:

41452

American (AMR)

AF:

0.250

AC:

3818

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

1085

AN:

3468

East Asian (EAS)

AF:

0.262

AC:

1354

AN:

5168

South Asian (SAS)

AF:

0.255

AC:

1228

AN:

4822

European-Finnish (FIN)

AF:

0.266

AC:

2815

AN:

10568

Middle Eastern (MID)

AF:

0.379

AC:

110

AN:

290

European-Non Finnish (NFE)

AF:

0.319

AC:

21662

AN:

67978

Other (OTH)

AF:

0.357

AC:

754

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1727

3455

5182

6910

8637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.330

Hom.:

20589

Bravo

AF:

0.353

Asia WGS

AF:

0.256

AC:

892

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.7

(source)

DANN

Benign

0.68

PhyloP100

0.15

PromoterAI

0.0046

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over