5-132861594-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Strong BP6_Moderate BS2

The NM_005260.7(GDF9):c.1360C>T(p.Arg454Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,613,354 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: GDF9 NM_005260.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.68

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 Benign. Variant got -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.03714037).
• BP6: Variant 5-132861594-G-A is Benign according to our data. Variant chr5-132861594-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2571230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF9	NM_005260.7	c.1360C>T	p.Arg454Cys	missense_variant	2/2	ENST00000687138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF9	ENST00000687138.1	c.1360C>T	p.Arg454Cys	missense_variant	2/2		NM_005260.7	P2

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00293 AC: 738 AN: 251482 Hom.: 1 AF XY: 0.00309 AC XY: 420 AN XY: 135916

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00378 AC: 5530 AN: 1461082 Hom.: 16 Cov.: 29 AF XY: 0.00385 AC XY: 2798 AN XY: 726888

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74458

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00394 Hom.: 2

Bravo AF: 0.00349

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00403

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

GDF9: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;.;.
MetaRNN	Benign	0.037	T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.5	H;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.0	D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.65
MVP		0.85
MPC		0.31
ClinPred		0.10	T
GERP RS		5.2
Varity_R		0.76
gMVP		0.79

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: rs61754582; hg19: chr5-132197286;