rs73488038

chrX-50916247-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005448.2(BMP15):c.819A>C(p.Ser273=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,208,992 control chromosomes in the GnomAD database, including 11 homozygotes. There are 418 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., 203 hem., cov: 22)
  • Exomes 𝑓: 0.00075 (4 hom. 215 hem.)
• Consequence: BMP15 NM_005448.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.421

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=-0.96).
• BP6: Variant X-50916247-A-C is Benign according to our data. Variant chrX-50916247-A-C is described in ClinVar as [Benign]. Clinvar id is 259776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.421 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (757/111157) while in subpopulation AFR AF= 0.0236 (720/30516). AF 95% confidence interval is 0.0222. There are 7 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.819A>C	p.Ser273=	synonymous_variant	2/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.819A>C	p.Ser273=	synonymous_variant	2/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 757 AN: 111104 Hom.: 7 Cov.: 22 AF XY: 0.00607 AC XY: 202 AN XY: 33300

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000389

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00332

GnomAD3 exomes AF: 0.00189 AC: 345 AN: 182951 Hom.: 1 AF XY: 0.00119 AC XY: 80 AN XY: 67451

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000876

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000748 AC: 821 AN: 1097835 Hom.: 4 Cov.: 32 AF XY: 0.000592 AC XY: 215 AN XY: 363203

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.000994

Gnomad4 ASJ exome AF: 0.000929

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000356

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00681 AC: 757 AN: 111157 Hom.: 7 Cov.: 22 AF XY: 0.00608 AC XY: 203 AN XY: 33363

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00239

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000390

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000754

Gnomad4 OTH AF: 0.00328

Alfa AF: 0.00384 Hom.: 16

Bravo AF: 0.00767

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.96
Cadd	Benign	0.31
Dann	Benign	0.45

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: rs73488038; hg19: chrX-50659247;