Genetic Variant GDF9:p.Thr149Thr (chr5-132862507-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_005260.7(GDF9):c.447C>T(p.Thr149Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,609,392 control chromosomes in the GnomAD database, including 255,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.50 ( 19760 hom., cov: 32)

Exomes 𝑓: 0.56 ( 235922 hom. )

Consequence

GDF9
NM_005260.7 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.249

Publications

43 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 5-132862507-G-A is Benign according to our data. Variant chr5-132862507-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232502.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.249 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 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	HGVSp	Effect	Exon Rank	Protein
GDF9	NM_005260.7	MANE Select	c.447C>T	p.Thr149Thr	synonymous	Exon 2 of 2	NP_005251.1
GDF9	NM_001288824.4		c.183C>T	p.Thr61Thr	synonymous	Exon 3 of 3	NP_001275753.1
GDF9	NM_001288825.4		c.183C>T	p.Thr61Thr	synonymous	Exon 4 of 4	NP_001275754.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GDF9	ENST00000687138.1	MANE Select	c.447C>T	p.Thr149Thr	synonymous	Exon 2 of 2	ENSP00000510441.1
GDF9	ENST00000378673.2	TSL:5	c.447C>T	p.Thr149Thr	synonymous	Exon 3 of 3	ENSP00000367942.2
GDF9	ENST00000464378.2	TSL:2	c.447C>T	p.Thr149Thr	synonymous	Exon 3 of 3	ENSP00000509893.1

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

75783

AN:

151874

Hom.:

19759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.358

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.597

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.617

Gnomad FIN

AF:

0.489

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.582

Gnomad OTH

AF:

0.501

GnomAD2 exomes

AF:

0.523

AC:

130153

AN:

248780

AF XY:

0.538

show subpopulations

Gnomad AFR exome

AF:

0.359

Gnomad AMR exome

AF:

0.444

Gnomad ASJ exome

AF:

0.592

Gnomad EAS exome

AF:

0.279

Gnomad FIN exome

AF:

0.493

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.536

GnomAD4 exome

AF:

0.565

AC:

823029

AN:

1457398

Hom.:

235922

Cov.:

AF XY:

0.567

AC XY:

411316

AN XY:

725352

show subpopulations

African (AFR)

AF:

0.364

AC:

12153

AN:

33410

American (AMR)

AF:

0.452

AC:

20231

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.594

AC:

15511

AN:

26128

East Asian (EAS)

AF:

0.325

AC:

12905

AN:

39682

South Asian (SAS)

AF:

0.632

AC:

54458

AN:

86210

European-Finnish (FIN)

AF:

0.484

AC:

25237

AN:

52168

Middle Eastern (MID)

AF:

0.546

AC:

3148

AN:

5768

European-Non Finnish (NFE)

AF:

0.583

AC:

646669

AN:

1109022

Other (OTH)

AF:

0.543

AC:

32717

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

19661

39322

58983

78644

98305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17676

35352

53028

70704

88380

<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:

0.499

AC:

75819

AN:

151994

Hom.:

19760

Cov.:

AF XY:

0.497

AC XY:

36915

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.358

AC:

14843

AN:

41462

American (AMR)

AF:

0.518

AC:

7902

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

2070

AN:

3470

East Asian (EAS)

AF:

0.291

AC:

1505

AN:

5166

South Asian (SAS)

AF:

0.616

AC:

2962

AN:

4810

European-Finnish (FIN)

AF:

0.489

AC:

5154

AN:

10544

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.582

AC:

39568

AN:

67954

Other (OTH)

AF:

0.504

AC:

1065

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1854

3708

5561

7415

9269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.552

Hom.:

46691

Bravo

AF:

0.488

Asia WGS

AF:

0.455

AC:

1584

AN:

3478

EpiCase

AF:

0.594

EpiControl

AF:

0.592

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16278619)

GDF9-related disorder

Benign:1

Jul 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.3

(source)

DANN

Benign

0.68

PhyloP100

-0.25

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over