rs104894763

Variant names:

• chrX-50910985-C-T
• rs104894763
• NM_005448.2:c.202C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_005448.2(BMP15):​c.202C>T​(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,190,144 control chromosomes in the GnomAD database, including 1 homozygotes. There are 422 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., 22 hem., cov: 24)
  • Exomes 𝑓: 0.0012 (1 hom. 400 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: 2.05
• Publications: 19 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3806206).
• BP6: Variant X-50910985-C-T is Benign according to our data. Variant chrX-50910985-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11474.
• BS2: High AC in GnomAd4 at 70 AD,XL 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	NM_005448.2	MANE Select	c.202C>T	p.Arg68Trp	missense	Exon 1 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.202C>T	p.Arg68Trp	missense	Exon 1 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 70 AN: 112256 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000700 AC: 101 AN: 144352 AF XY: 0.000681

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.000254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.000263

GnomAD4 exome AF: 0.00116 AC: 1251 AN: 1077837 Hom.: 1 Cov.: 33 AF XY: 0.00114 AC XY: 400 AN XY: 350677

African (AFR) AF: 0.000347 AC: 9 AN: 25902

American (AMR) AF: 0.000432 AC: 14 AN: 32381

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18991

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29050

South Asian (SAS) AF: 0.000194 AC: 10 AN: 51455

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39165

Middle Eastern (MID) AF: 0.000248 AC: 1 AN: 4026

European-Non Finnish (NFE) AF: 0.00140 AC: 1166 AN: 831535

Other (OTH) AF: 0.00110 AC: 50 AN: 45332

GnomAD4 genome AF: 0.000623 AC: 70 AN: 112307 Hom.: 0 Cov.: 24 AF XY: 0.000638 AC XY: 22 AN XY: 34489

African (AFR) AF: 0.000129 AC: 4 AN: 30978

American (AMR) AF: 0.000562 AC: 6 AN: 10672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00109 AC: 58 AN: 53213

Other (OTH) AF: 0.00130 AC: 2 AN: 1537

Alfa AF: 0.000900 Hom.: 39

Bravo AF: 0.000763

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00178 AC: 12

ExAC AF: 0.000535 AC: 64

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	BMP15-related disorder (1)
-	-	1	Ovarian dysgenesis 2 (1)
1	-	-	Premature ovarian failure 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.15
MVP		0.97
MPC		0.16
ClinPred		0.082	T
GERP RS		1.8
PromoterAI		-0.077	Neutral
Varity_R		0.19
gMVP		0.67
Mutation Taster		=73/27	polymorphism

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: rs104894763; hg19: chrX-50653985;