rs254286

Variant names:

• chr5-132862507-G-A
• rs254286
• NM_005260.7:c.447C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-132862507-G-A
• chr5-132862507-G-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.249
• Publications: 43 publications found

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)

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF9	NM_005260.7	c.447C>T	p.Thr149Thr	synonymous_variant	Exon 2 of 2	ENST00000687138.1	NP_005251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF9	ENST00000687138.1	c.447C>T	p.Thr149Thr	synonymous_variant	Exon 2 of 2		NM_005260.7	ENSP00000510441.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75783 AN: 151874 Hom.: 19759 Cov.: 32

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

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.: 34 AF XY: 0.567 AC XY: 411316 AN XY: 725352

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

GnomAD4 genome AF: 0.499 AC: 75819 AN: 151994 Hom.: 19760 Cov.: 32 AF XY: 0.497 AC XY: 36915 AN XY: 74266

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

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

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
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs254286; hg19: chr5-132198199; COSMIC: COSV51526297; COSMIC: COSV51526297;