chr5-132862595-C-G

Variant names:

• chr5-132862595-C-G
• rs254285
• NM_005260.7:c.398-39G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005260.7(GDF9):​c.398-39G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,531,450 control chromosomes in the GnomAD database, including 604,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (60600 hom., cov: 30)
  • Exomes 𝑓: 0.88 (543752 hom.)
• Consequence: GDF9 NM_005260.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.469
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-132862595-C-G is Benign according to our data. Variant chr5-132862595-C-G is described in ClinVar as Benign. ClinVar VariationId is 1232056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF9	NM_005260.7	c.398-39G>C		intron_variant	Intron 1 of 1	ENST00000687138.1	NP_005251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF9	ENST00000687138.1	c.398-39G>C		intron_variant	Intron 1 of 1		NM_005260.7	ENSP00000510441.1

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134830 AN: 151984 Hom.: 60544 Cov.: 30

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.918

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.888

GnomAD2 exomes AF: 0.828 AC: 191959 AN: 231764 AF XY: 0.840

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.629

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.754

Gnomad NFE exome AF: 0.900

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.884 AC: 1219690 AN: 1379350 Hom.: 543752 Cov.: 22 AF XY: 0.886 AC XY: 612272 AN XY: 690864

African (AFR) AF: 0.981 AC: 31557 AN: 32154

American (AMR) AF: 0.649 AC: 28837 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23453 AN: 25672

East Asian (EAS) AF: 0.587 AC: 23131 AN: 39394

South Asian (SAS) AF: 0.891 AC: 75076 AN: 84304

European-Finnish (FIN) AF: 0.762 AC: 30153 AN: 39592

Middle Eastern (MID) AF: 0.927 AC: 4984 AN: 5376

European-Non Finnish (NFE) AF: 0.906 AC: 951746 AN: 1050474

Other (OTH) AF: 0.876 AC: 50753 AN: 57932

GnomAD4 genome AF: 0.887 AC: 134945 AN: 152100 Hom.: 60600 Cov.: 30 AF XY: 0.878 AC XY: 65219 AN XY: 74310

African (AFR) AF: 0.975 AC: 40500 AN: 41518

American (AMR) AF: 0.783 AC: 11970 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3160 AN: 3470

East Asian (EAS) AF: 0.556 AC: 2864 AN: 5152

South Asian (SAS) AF: 0.871 AC: 4200 AN: 4822

European-Finnish (FIN) AF: 0.755 AC: 7964 AN: 10550

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61303 AN: 67992

Other (OTH) AF: 0.886 AC: 1874 AN: 2114

Alfa AF: 0.896 Hom.: 11264

Bravo AF: 0.888

Asia WGS AF: 0.721 AC: 2511 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.30
DANN	Benign	0.56
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs254285; hg19: chr5-132198287; COSMIC: COSV51526807; COSMIC: COSV51526807;