dbSNP rs254285: GDF9:c.398-39G>C (chr5-132862595-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005260.7(GDF9):c.398-39G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,531,450 control chromosomes in the GnomAD database, including 604,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.89 ( 60600 hom., cov: 30)

Exomes 𝑓: 0.88 ( 543752 hom. )

Consequence

GDF9
NM_005260.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.469

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-132862595-C-G is Benign according to our data. Variant chr5-132862595-C-G is described in ClinVar as Benign. ClinVar VariationId is 1232056.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF9	NM_005260.7	MANE Select	c.398-39G>C	intron	N/A	NP_005251.1	O60383
GDF9	NM_001288824.4		c.134-39G>C	intron	N/A	NP_001275753.1	B4DXG3
GDF9	NM_001288825.4		c.134-39G>C	intron	N/A	NP_001275754.1	B4DXG3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF9	ENST00000687138.1	MANE Select	c.398-39G>C	intron	N/A	ENSP00000510441.1	O60383
GDF9	ENST00000378673.2	TSL:5	c.398-39G>C	intron	N/A	ENSP00000367942.2	O60383
GDF9	ENST00000464378.2	TSL:2	c.398-39G>C	intron	N/A	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes

AF:

0.887

AC:

134830

AN:

151984

Hom.:

60544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.975

Gnomad AMI

AF:

0.918

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.911

Gnomad EAS

AF:

0.556

Gnomad SAS

AF:

0.870

Gnomad FIN

AF:

0.755

Gnomad MID

AF:

0.930

Gnomad NFE

AF:

0.902

Gnomad OTH

AF:

0.888

GnomAD2 exomes

AF:

0.828

AC:

191959

AN:

231764

AF XY:

0.840

show subpopulations

Gnomad AFR exome

AF:

0.979

Gnomad AMR exome

AF:

0.629

Gnomad ASJ exome

AF:

0.913

Gnomad EAS exome

AF:

0.543

Gnomad FIN exome

AF:

0.754

Gnomad NFE exome

AF:

0.900

Gnomad OTH exome

AF:

0.863

GnomAD4 exome

AF:

0.884

AC:

1219690

AN:

1379350

Hom.:

543752

Cov.:

AF XY:

0.886

AC XY:

612272

AN XY:

690864

show subpopulations

African (AFR)

AF:

0.981

AC:

31557

AN:

32154

American (AMR)

AF:

0.649

AC:

28837

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

23453

AN:

25672

East Asian (EAS)

AF:

0.587

AC:

23131

AN:

39394

South Asian (SAS)

AF:

0.891

AC:

75076

AN:

84304

European-Finnish (FIN)

AF:

0.762

AC:

30153

AN:

39592

Middle Eastern (MID)

AF:

0.927

AC:

4984

AN:

5376

European-Non Finnish (NFE)

AF:

0.906

AC:

951746

AN:

1050474

Other (OTH)

AF:

0.876

AC:

50753

AN:

57932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

5804

11608

17412

23216

29020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19750

39500

59250

79000

98750

<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:

0.887

AC:

134945

AN:

152100

Hom.:

60600

Cov.:

AF XY:

0.878

AC XY:

65219

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.975

AC:

40500

AN:

41518

American (AMR)

AF:

0.783

AC:

11970

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.911

AC:

3160

AN:

3470

East Asian (EAS)

AF:

0.556

AC:

2864

AN:

5152

South Asian (SAS)

AF:

0.871

AC:

4200

AN:

4822

European-Finnish (FIN)

AF:

0.755

AC:

7964

AN:

10550

Middle Eastern (MID)

AF:

0.935

AC:

275

AN:

294

European-Non Finnish (NFE)

AF:

0.902

AC:

61303

AN:

67992

Other (OTH)

AF:

0.886

AC:

1874

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

702

1403

2105

2806

3508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.896

Hom.:

11264

Bravo

AF:

0.888

Asia WGS

AF:

0.721

AC:

2511

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.30

(source)

DANN

Benign

0.56

PhyloP100

-0.47

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over