Genetic Variant GDF9:c.-1193C>T (chr5-132865726-G-A) – 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.-1193C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 151,974 control chromosomes in the GnomAD database, including 19,537 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 0.49 ( 19536 hom., cov: 31)

Exomes 𝑓: 0.50 ( 1 hom. )

Consequence

GDF9
NM_005260.7 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0420

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: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

GDF9 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005260.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.81).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.599 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.-1193C>T	5_prime_UTR	Exon 1 of 2	NP_005251.1	O60383
GDF9	NM_001288824.4		c.-32+873C>T	intron	N/A	NP_001275753.1	B4DXG3
GDF9	NM_001288825.4		c.-147-254C>T	intron	N/A	NP_001275754.1	B4DXG3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GDF9	ENST00000687138.1	MANE Select	c.-1193C>T	5_prime_UTR	Exon 1 of 2	ENSP00000510441.1	O60383
GDF9	ENST00000464378.2	TSL:2	c.-1118C>T	5_prime_UTR	Exon 1 of 3	ENSP00000509893.1	O60383
GDF9	ENST00000621295.5	TSL:5	c.-334C>T	5_prime_UTR	Exon 1 of 3	ENSP00000484339.1	B4DXG3

Frequencies

GnomAD3 genomes

AF:

0.494

AC:

75064

AN:

151846

Hom.:

19535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.335

Gnomad AMI

AF:

0.651

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.598

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.498

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.496

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

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)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.494

AC:

75098

AN:

151964

Hom.:

19536

Cov.:

AF XY:

0.493

AC XY:

36604

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.335

AC:

13866

AN:

41418

American (AMR)

AF:

0.517

AC:

7888

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.598

AC:

2071

AN:

3464

East Asian (EAS)

AF:

0.319

AC:

1644

AN:

5160

South Asian (SAS)

AF:

0.617

AC:

2970

AN:

4812

European-Finnish (FIN)

AF:

0.498

AC:

5258

AN:

10558

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39599

AN:

67968

Other (OTH)

AF:

0.498

AC:

1050

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1903

3807

5710

7614

9517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.548

Hom.:

64483

Bravo

AF:

0.482

Asia WGS

AF:

0.469

AC:

1630

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.7

(source)

DANN

Benign

0.62

PhyloP100

0.042

PromoterAI

0.031

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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