rs112064937

Variant names:

• chrX-50916620-G-A
• rs112064937
• NM_005448.2:c.*13G>A

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1624 XL,AD gene.

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.*13G>A		3_prime_UTR	Exon 2 of 2	NP_005439.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	ENST00000252677.4	TSL:1 MANE Select	c.*13G>A		3_prime_UTR	Exon 2 of 2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 1623 AN: 111234 Hom.: 35 Cov.: 22

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

GnomAD2 exomes AF: 0.00439 AC: 793 AN: 180830 AF XY: 0.00266

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 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

African (AFR) AF: 0.0508 AC: 1339 AN: 26378

American (AMR) AF: 0.00284 AC: 100 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30198

South Asian (SAS) AF: 0.0000556 AC: 3 AN: 53998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.00218 AC: 8 AN: 3663

European-Non Finnish (NFE) AF: 0.0000428 AC: 36 AN: 841819

Other (OTH) AF: 0.00389 AC: 179 AN: 46026

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

African (AFR) AF: 0.0497 AC: 1521 AN: 30578

American (AMR) AF: 0.00747 AC: 78 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5977

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53135

Other (OTH) AF: 0.0132 AC: 20 AN: 1518

Alfa AF: 0.00790 Hom.: 38

Bravo AF: 0.0164

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ovarian dysgenesis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.56
DANN	Benign	0.22
PhyloP100		-0.74

Splicing

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

Other links and lift over

dbSNP: rs112064937; hg19: chrX-50659620;