rs17003221

chrX-50916280-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005448.2(BMP15):c.852C>T(p.Ser284=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,204,453 control chromosomes in the GnomAD database, including 4,695 homozygotes. There are 12,892 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2306 hom., 4061 hem., cov: 22)
  • Exomes 𝑓: 0.024 (2389 hom. 8831 hem.)
• Consequence: BMP15 NM_005448.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.249

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-50916280-C-T is Benign according to our data. Variant chrX-50916280-C-T is described in ClinVar as [Benign]. Clinvar id is 259777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.249 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.852C>T	p.Ser284=	synonymous_variant	2/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.852C>T	p.Ser284=	synonymous_variant	2/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 15016 AN: 110635 Hom.: 2307 Cov.: 22 AF XY: 0.123 AC XY: 4052 AN XY: 32901

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0194

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.0910

Gnomad FIN AF: 0.000335

Gnomad MID AF: 0.0591

Gnomad NFE AF: 0.00477

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0581 AC: 10426 AN: 179550 Hom.: 1147 AF XY: 0.0490 AC XY: 3154 AN XY: 64306

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.0652

Gnomad SAS exome AF: 0.0972

Gnomad FIN exome AF: 0.0000635

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0237 AC: 25942 AN: 1093762 Hom.: 2389 Cov.: 32 AF XY: 0.0246 AC XY: 8831 AN XY: 359690

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.0454

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0699

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.136 AC: 15023 AN: 110691 Hom.: 2306 Cov.: 22 AF XY: 0.123 AC XY: 4061 AN XY: 32967

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.0603

Gnomad4 ASJ AF: 0.0194

Gnomad4 EAS AF: 0.0647

Gnomad4 SAS AF: 0.0897

Gnomad4 FIN AF: 0.000335

Gnomad4 NFE AF: 0.00477

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0384 Hom.: 1140

Bravo AF: 0.155

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	Sep 29, 2015	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 13, 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	-0.90
Cadd	Benign	0.25
Dann	Benign	0.40

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: rs17003221; hg19: chrX-50659280; COSMIC: COSV53139908;