rs112064937

Positions:

• chrX-50916620-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005448.2(BMP15):​c.*13G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,208,451 control chromosomes in the GnomAD database, including 63 homozygotes. There are 872 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (36 hom., 441 hem., cov: 22)
  • Exomes 𝑓: 0.0015 (27 hom. 431 hem.)
• Consequence: BMP15 NM_005448.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.737

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-50916620-G-A is Benign according to our data. Variant chrX-50916620-G-A is described in ClinVar as [Benign]. Clinvar id is 259773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (1624/111287) while in subpopulation AFR AF= 0.0497 (1521/30578). AF 95% confidence interval is 0.0477. There are 36 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.*13G>A		3_prime_UTR_variant	2/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.*13G>A		3_prime_UTR_variant	2/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 1623 AN: 111234 Hom.: 35 Cov.: 22 AF XY: 0.0132 AC XY: 442 AN XY: 33444

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00748

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000386

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.0133

GnomAD3 exomes AF: 0.00439 AC: 793 AN: 180830 Hom.: 18 AF XY: 0.00266 AC XY: 178 AN XY: 66878

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00152 AC: 1667 AN: 1097164 Hom.: 27 Cov.: 31 AF XY: 0.00119 AC XY: 431 AN XY: 362818

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000428

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.0146 AC: 1624 AN: 111287 Hom.: 36 Cov.: 22 AF XY: 0.0132 AC XY: 441 AN XY: 33507

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.00747

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00790 Hom.: 38

Bravo AF: 0.0164

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	GeneDx	Dec 01, 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. -
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 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	-0.92
CADD	Benign	0.56
DANN	Benign	0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112064937; hg19: chrX-50659620;