rs73488038

Variant names:

• chrX-50916247-A-C
• rs73488038
• NM_005448.2:c.819A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005448.2(BMP15):​c.819A>C​(p.Ser273Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,208,992 control chromosomes in the GnomAD database, including 11 homozygotes. There are 418 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., 203 hem., cov: 22)
  • Exomes 𝑓: 0.00075 (4 hom. 215 hem.)
• Consequence: BMP15 NM_005448.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.421
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant X-50916247-A-C is Benign according to our data. Variant chrX-50916247-A-C is described in ClinVar as Benign. ClinVar VariationId is 259776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.421 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00681 (757/111157) while in subpopulation AFR AF = 0.0236 (720/30516). AF 95% confidence interval is 0.0222. There are 7 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 757 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.819A>C	p.Ser273Ser	synonymous	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.819A>C	p.Ser273Ser	synonymous	Exon 2 of 2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 757 AN: 111104 Hom.: 7 Cov.: 22

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000389

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00332

GnomAD2 exomes AF: 0.00189 AC: 345 AN: 182951 AF XY: 0.00119

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000876

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000748 AC: 821 AN: 1097835 Hom.: 4 Cov.: 32 AF XY: 0.000592 AC XY: 215 AN XY: 363203

African (AFR) AF: 0.0238 AC: 629 AN: 26394

American (AMR) AF: 0.000994 AC: 35 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.000929 AC: 18 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00218 AC: 9 AN: 4136

European-Non Finnish (NFE) AF: 0.0000356 AC: 30 AN: 841848

Other (OTH) AF: 0.00213 AC: 98 AN: 46080

GnomAD4 genome AF: 0.00681 AC: 757 AN: 111157 Hom.: 7 Cov.: 22 AF XY: 0.00608 AC XY: 203 AN XY: 33363

African (AFR) AF: 0.0236 AC: 720 AN: 30516

American (AMR) AF: 0.00239 AC: 25 AN: 10452

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.000390 AC: 1 AN: 2562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5979

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0000754 AC: 4 AN: 53044

Other (OTH) AF: 0.00328 AC: 5 AN: 1523

Alfa AF: 0.00384 Hom.: 16

Bravo AF: 0.00767

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Ovarian dysgenesis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.31
DANN	Benign	0.45
PhyloP100		-0.42
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: rs73488038; hg19: chrX-50659247;