rs371124071

Variant names:

• chrX-50916210-C-CTCT
• rs371124071
• NM_005448.2:c.786_788dupTCT

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_005448.2(BMP15):​c.786_788dupTCT​(p.Leu263dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,208,442 control chromosomes in the GnomAD database, including 4,697 homozygotes. There are 12,745 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2285 hom., 3760 hem., cov: 18)
  • Exomes 𝑓: 0.024 (2412 hom. 8985 hem.)
• Consequence: BMP15 NM_005448.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.176
• Publications: 2 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: AD, XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005448.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-50916210-C-CTCT is Benign according to our data. Variant chrX-50916210-C-CTCT is described in ClinVar as Benign. ClinVar VariationId is 259775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	NM_005448.2	MANE Select	c.786_788dupTCT	p.Leu263dup	disruptive_inframe_insertion	Exon 2 of 2	NP_005439.2	O95972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	ENST00000252677.4	TSL:1 MANE Select	c.786_788dupTCT	p.Leu263dup	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14660 AN: 110247 Hom.: 2286 Cov.: 18

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0186

Gnomad EAS AF: 0.0638

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.000500

Gnomad MID AF: 0.0551

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.0577 AC: 10570 AN: 183113 AF XY: 0.0483

Gnomad AFR exome AF: 0.455

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.0647

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0239 AC: 26227 AN: 1098141 Hom.: 2412 Cov.: 32 AF XY: 0.0247 AC XY: 8985 AN XY: 363509

African (AFR) AF: 0.449 AC: 11858 AN: 26392

American (AMR) AF: 0.0451 AC: 1588 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 362 AN: 19385

East Asian (EAS) AF: 0.0698 AC: 2108 AN: 30197

South Asian (SAS) AF: 0.103 AC: 5572 AN: 54132

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40528

Middle Eastern (MID) AF: 0.0503 AC: 208 AN: 4137

European-Non Finnish (NFE) AF: 0.00293 AC: 2470 AN: 842091

Other (OTH) AF: 0.0446 AC: 2056 AN: 46088

GnomAD4 genome AF: 0.133 AC: 14666 AN: 110301 Hom.: 2285 Cov.: 18 AF XY: 0.115 AC XY: 3760 AN XY: 32651

African (AFR) AF: 0.441 AC: 13145 AN: 29807

American (AMR) AF: 0.0586 AC: 609 AN: 10391

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 49 AN: 2636

East Asian (EAS) AF: 0.0631 AC: 221 AN: 3501

South Asian (SAS) AF: 0.0891 AC: 225 AN: 2525

European-Finnish (FIN) AF: 0.000500 AC: 3 AN: 5996

Middle Eastern (MID) AF: 0.0558 AC: 12 AN: 215

European-Non Finnish (NFE) AF: 0.00470 AC: 249 AN: 53032

Other (OTH) AF: 0.101 AC: 153 AN: 1516

Alfa AF: 0.0564 Hom.: 560

Asia WGS AF: 0.115 AC: 294 AN: 2522

EpiCase AF: 0.00638

EpiControl AF: 0.00725

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Ovarian dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=81/19	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs371124071; hg19: chrX-50659210; COSMIC: COSV53140428;