rs12687730

Variant names:

• chrX-50911598-T-C
• rs12687730
• NM_005448.2:c.328+487T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005448.2(BMP15):​c.328+487T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 111,644 control chromosomes in the GnomAD database, including 57 homozygotes. There are 938 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.026 (57 hom., 938 hem., cov: 23)
• Consequence: BMP15 NM_005448.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• Publications: 1 publications found

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]

BMP15 Gene-Disease associations (from GenCC):

• ovarian dysgenesis 2

  Inheritance: XL, AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005448.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	NM_005448.2	MANE Select	c.328+487T>C		intron	N/A	NP_005439.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	ENST00000252677.4	TSL:1 MANE Select	c.328+487T>C		intron	N/A	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 2915 AN: 111589 Hom.: 57 Cov.: 23

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00808

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.0753

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.0160

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0262 AC: 2925 AN: 111644 Hom.: 57 Cov.: 23 AF XY: 0.0277 AC XY: 938 AN XY: 33840

African (AFR) AF: 0.0700 AC: 2148 AN: 30664

American (AMR) AF: 0.00807 AC: 85 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.0505 AC: 178 AN: 3527

South Asian (SAS) AF: 0.0752 AC: 197 AN: 2621

European-Finnish (FIN) AF: 0.0322 AC: 194 AN: 6029

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00173 AC: 92 AN: 53194

Other (OTH) AF: 0.0197 AC: 30 AN: 1521

Alfa AF: 0.0133 Hom.: 147

Bravo AF: 0.0263

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.58
PhyloP100		0.016
Mutation Taster		=100/0	polymorphism (auto)

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: rs12687730; hg19: chrX-50654598;