Genetic Variant GDF9:p.Arg454Cys (chr5-132861594-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_005260.7(GDF9):c.1360C>T(p.Arg454Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,613,354 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 16 hom. )

Consequence

GDF9
NM_005260.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.68

Publications

15 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 -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.03714037).

BP6

Variant 5-132861594-G-A is Benign according to our data. Variant chr5-132861594-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2571230.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

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	UniProt
GDF9	NM_005260.7	MANE Select	c.1360C>T	p.Arg454Cys	missense	Exon 2 of 2	NP_005251.1	O60383
GDF9	NM_001288824.4		c.1096C>T	p.Arg366Cys	missense	Exon 3 of 3	NP_001275753.1	B4DXG3
GDF9	NM_001288825.4		c.1096C>T	p.Arg366Cys	missense	Exon 4 of 4	NP_001275754.1	B4DXG3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDF9	ENST00000687138.1	MANE Select	c.1360C>T	p.Arg454Cys	missense	Exon 2 of 2	ENSP00000510441.1	O60383
GDF9	ENST00000378673.2	TSL:5	c.1360C>T	p.Arg454Cys	missense	Exon 3 of 3	ENSP00000367942.2	O60383
GDF9	ENST00000464378.2	TSL:2	c.1360C>T	p.Arg454Cys	missense	Exon 3 of 3	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

467

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00293

AC:

738

AN:

251482

AF XY:

0.00309

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00378

AC:

5530

AN:

1461082

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

2798

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33466

American (AMR)

AF:

0.00295

AC:

132

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000918

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00273

AC:

235

AN:

86132

European-Finnish (FIN)

AF:

0.00361

AC:

193

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00424

AC:

4717

AN:

1111360

Other (OTH)

AF:

0.00323

AC:

195

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

251

502

754

1005

1256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<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:

0.00307

AC:

467

AN:

152272

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41558

American (AMR)

AF:

0.00745

AC:

114

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00418

AC:

284

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00294

AC:

357

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00403

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.037

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.5

PhyloP100

7.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.65

MVP

0.85

MPC

0.31

ClinPred

0.10

GERP RS

5.2

Varity_R

0.76

gMVP

0.79

Mutation Taster

=91/9

polymorphism

(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