NM_005260.7:c.1333G>A

Variant names:

• chr5-132861621-C-T
• rs774616473
• NM_005260.7:c.1333G>A

Variant summary

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

The NM_005260.7(GDF9):​c.1333G>A​(p.Asp445Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,612,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: GDF9 NM_005260.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• Publications: 1 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 0 ACMG points.

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.1333G>A	p.Asp445Asn	missense	Exon 2 of 2	NP_005251.1	O60383
	GDF9	NM_001288824.4		c.1069G>A	p.Asp357Asn	missense	Exon 3 of 3	NP_001275753.1	B4DXG3
	GDF9	NM_001288825.4		c.1069G>A	p.Asp357Asn	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.1333G>A	p.Asp445Asn	missense	Exon 2 of 2	ENSP00000510441.1	O60383
	GDF9	ENST00000378673.2	TSL:5	c.1333G>A	p.Asp445Asn	missense	Exon 3 of 3	ENSP00000367942.2	O60383
	GDF9	ENST00000464378.2	TSL:2	c.1333G>A	p.Asp445Asn	missense	Exon 3 of 3	ENSP00000509893.1	O60383

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251486 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1460730 Hom.: 0 Cov.: 28 AF XY: 0.0000261 AC XY: 19 AN XY: 726774

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1110934

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Benign	0.075	T
Sift4G	Benign	0.27	T
Polyphen		0.71	P
Vest4		0.24
MVP		0.97
MPC		0.19
ClinPred		0.43	T
GERP RS		5.3
Varity_R		0.21
gMVP		0.69
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: rs774616473; hg19: chr5-132197313; COSMIC: COSV51526233; COSMIC: COSV51526233;