Genetic Variant GDF9:c.-1005A>G (chr5-132865538-T-C) – 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.-1005A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 151,920 control chromosomes in the GnomAD database, including 9,580 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 0.34 ( 9578 hom., cov: 31)

Exomes 𝑓: 0.43 ( 2 hom. )

Consequence

GDF9
NM_005260.7 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.856

Publications

5 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=-0.89).

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.-1005A>G		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.-1005A>G		5_prime_UTR_variant	Exon 1 of 2		NM_005260.7	ENSP00000510441.1		O60383

Frequencies

GnomAD3 genomes

AF:

0.343

AC:

52091

AN:

151788

Hom.:

9566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.211

Gnomad MID

AF:

0.381

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.357

GnomAD4 exome

AF:

0.429

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.343

AC:

52141

AN:

151906

Hom.:

9578

Cov.:

AF XY:

0.335

AC XY:

24848

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.479

AC:

19819

AN:

41394

American (AMR)

AF:

0.250

AC:

3805

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1078

AN:

3464

East Asian (EAS)

AF:

0.256

AC:

1321

AN:

5164

South Asian (SAS)

AF:

0.254

AC:

1222

AN:

4808

European-Finnish (FIN)

AF:

0.211

AC:

2230

AN:

10552

Middle Eastern (MID)

AF:

0.379

AC:

110

AN:

290

European-Non Finnish (NFE)

AF:

0.317

AC:

21567

AN:

67970

Other (OTH)

AF:

0.354

AC:

746

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1687

3374

5060

6747

8434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.328

Hom.:

1063

Bravo

AF:

0.353

Asia WGS

AF:

0.247

AC:

863

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.5

(source)

DANN

Benign

0.47

PhyloP100

-0.86

PromoterAI

0.0057

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over