5-132861826-C-G

Variant names:

• chr5-132861826-C-G
• rs141185638
• NM_005260.7:c.1128G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005260.7(GDF9):​c.1128G>C​(p.Arg376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GDF9 NM_005260.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF9	NM_005260.7	MANE Select	c.1128G>C	p.Arg376Ser	missense	Exon 2 of 2	NP_005251.1	O60383
	GDF9	NM_001288824.4		c.864G>C	p.Arg288Ser	missense	Exon 3 of 3	NP_001275753.1	B4DXG3
	GDF9	NM_001288825.4		c.864G>C	p.Arg288Ser	missense	Exon 4 of 4	NP_001275754.1	B4DXG3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF9	ENST00000687138.1	MANE Select	c.1128G>C	p.Arg376Ser	missense	Exon 2 of 2	ENSP00000510441.1	O60383
	GDF9	ENST00000378673.2	TSL:5	c.1128G>C	p.Arg376Ser	missense	Exon 3 of 3	ENSP00000367942.2	O60383
	GDF9	ENST00000464378.2	TSL:2	c.1128G>C	p.Arg376Ser	missense	Exon 3 of 3	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	0.00051	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.0
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.60		Loss of MoRF binding (P = 0.04)
MVP		0.93
MPC		0.12
ClinPred		0.99	D
GERP RS		-5.6
Varity_R		0.64
gMVP		0.70
Mutation Taster		=65/35	polymorphism

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: rs141185638; hg19: chr5-132197518;