rs3810682

chrX-50910775-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005448.2(BMP15):c.-9C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,198,204 control chromosomes in the GnomAD database, including 18,782 homozygotes. There are 80,825 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1566 hom., 6090 hem., cov: 23)
  • Exomes 𝑓: 0.21 (17216 hom. 74735 hem.)
• Consequence: BMP15 NM_005448.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25

Genes affected

BMP15 (HGNC:1068): (bone morphogenetic protein 15) 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 subunits of a disulfide-linked homodimer, or alternatively, a heterodimer, with the related protein, growth differentiation factor 9 (GDF9). This protein plays a role in oocyte maturation and follicular development, through activation of granulosa cells. Defects in this gene are the cause of ovarian dysgenesis and are associated with premature ovarian failure. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-50910775-C-G is Benign according to our data. Variant chrX-50910775-C-G is described in ClinVar as [Benign]. Clinvar id is 136522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.-9C>G		5_prime_UTR_variant	1/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.-9C>G		5_prime_UTR_variant	1/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 21086 AN: 111376 Hom.: 1567 Cov.: 23 AF XY: 0.181 AC XY: 6084 AN XY: 33598

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.162 AC: 26645 AN: 163988 Hom.: 1819 AF XY: 0.154 AC XY: 8120 AN XY: 52724

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0845

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0295

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.211 AC: 229503 AN: 1086775 Hom.: 17216 Cov.: 31 AF XY: 0.211 AC XY: 74735 AN XY: 354563

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.0905

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.0525

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.189 AC: 21089 AN: 111429 Hom.: 1566 Cov.: 23 AF XY: 0.181 AC XY: 6090 AN XY: 33661

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.0394

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.159

Alfa AF: 0.216 Hom.: 5885

Bravo AF: 0.184

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ovarian dysgenesis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.7
Dann	Benign	0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3810682; hg19: chrX-50653775; COSMIC: COSV53141027;