5-132861722-T-C

Variant names:

• chr5-132861722-T-C
• rs1759246501
• NM_005260.7:c.1232A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005260.7(GDF9):​c.1232A>G​(p.Asp411Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GDF9 NM_005260.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF9	NM_005260.7	c.1232A>G	p.Asp411Gly	missense_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.1232A>G	p.Asp411Gly	missense_variant	Exon 2 of 2		NM_005260.7	ENSP00000510441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460122 Hom.: 0 Cov.: 28 AF XY: 0.00000688 AC XY: 5 AN XY: 726460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1232A>G (p.D411G) alteration is located in exon 2 (coding exon 2) of the GDF9 gene. This alteration results from a A to G substitution at nucleotide position 1232, causing the aspartic acid (D) at amino acid position 411 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;.;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.5	D;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0050	D;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.74
MutPred		0.60		Gain of methylation at K409 (P = 0.05);.;.;.;.;
MVP		0.97
MPC		0.29
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.87
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs1759246501; hg19: chr5-132197414;