rs371124071

chrX-50916210-C-CTCT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_005448.2(BMP15):c.786_788dup(p.Leu262dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.176

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.786_788dup	p.Leu262dup	inframe_insertion	2/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.786_788dup	p.Leu262dup	inframe_insertion	2/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14660 AN: 110247 Hom.: 2286 Cov.: 18 AF XY: 0.115 AC XY: 3752 AN XY: 32587

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

GnomAD3 exomes AF: 0.0577 AC: 10570 AN: 183113 Hom.: 1148 AF XY: 0.0483 AC XY: 3262 AN XY: 67603

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 SAS exome AF: 0.0997

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

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0187

Gnomad4 EAS exome AF: 0.0698

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.0446

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

Gnomad4 AFR AF: 0.441

Gnomad4 AMR AF: 0.0586

Gnomad4 ASJ AF: 0.0186

Gnomad4 EAS AF: 0.0631

Gnomad4 SAS AF: 0.0891

Gnomad4 FIN AF: 0.000500

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0564 Hom.: 560

Asia WGS AF: 0.115 AC: 294 AN: 2522

EpiCase AF: 0.00638

EpiControl AF: 0.00725

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2015

This variant is associated with the following publications: (PMID: 16508750, 25954833) -

Ovarian dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs371124071; hg19: chrX-50659210;