dbSNP rs254286: GDF9:p.Thr149Thr (chr5-132862507-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF9	NM_005260.7 link	c.447C>T	p.Thr149Thr	synonymous_variant	Exon 2 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.447C>T	p.Thr149Thr	synonymous_variant	Exon 2 of 2		NM_005260.7	ENSP00000510441.1		O60383

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

GnomAD3 exomes

AF:

0.523

AC:

130153

AN:

248780

Hom.:

35528

AF XY:

0.538

AC XY:

72569

AN XY:

134994

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 SAS exome

AF:

0.631

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

Gnomad4 AFR exome

AF:

0.364

Gnomad4 AMR exome

AF:

0.452

Gnomad4 ASJ exome

AF:

0.594

Gnomad4 EAS exome

AF:

0.325

Gnomad4 SAS exome

AF:

0.632

Gnomad4 FIN exome

AF:

0.484

Gnomad4 NFE exome

AF:

0.583

Gnomad4 OTH exome

AF:

0.543

GnomAD4 genome

AF:

0.499

AC:

75819

AN:

151994

Hom.:

19760

Cov.:

AF XY:

0.497

AC XY:

36915

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.358

Gnomad4 AMR

AF:

0.518

Gnomad4 ASJ

AF:

0.597

Gnomad4 EAS

AF:

0.291

Gnomad4 SAS

AF:

0.616

Gnomad4 FIN

AF:

0.489

Gnomad4 NFE

AF:

0.582

Gnomad4 OTH

AF:

0.504

Alfa

AF:

0.568

Hom.:

37895

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.3

DANN

Benign

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over