rs104894766

Variant names:

• chrX-50911009-C-T
• rs104894766
• NM_005448.2:c.226C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_005448.2(BMP15):​c.226C>T​(p.Arg76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,193,726 control chromosomes in the GnomAD database, including 1 homozygotes. There are 114 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 0.00032 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00016 (1 hom. 94 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.51
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant X-50911009-C-T is Pathogenic according to our data. Variant chrX-50911009-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11471.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11782113). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 36 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.226C>T	p.Arg76Cys	missense	Exon 1 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.226C>T	p.Arg76Cys	missense	Exon 1 of 2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 36 AN: 112258 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000712

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000413 AC: 62 AN: 150151 AF XY: 0.000699

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000862

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000258

GnomAD4 exome AF: 0.000164 AC: 177 AN: 1081412 Hom.: 1 Cov.: 33 AF XY: 0.000267 AC XY: 94 AN XY: 352434

African (AFR) AF: 0.000500 AC: 13 AN: 25998

American (AMR) AF: 0.0000301 AC: 1 AN: 33173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19030

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29263

South Asian (SAS) AF: 0.00284 AC: 147 AN: 51733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39235

Middle Eastern (MID) AF: 0.000496 AC: 2 AN: 4032

European-Non Finnish (NFE) AF: 0.00000600 AC: 5 AN: 833505

Other (OTH) AF: 0.000176 AC: 8 AN: 45443

GnomAD4 genome AF: 0.000321 AC: 36 AN: 112314 Hom.: 0 Cov.: 24 AF XY: 0.000580 AC XY: 20 AN XY: 34504

African (AFR) AF: 0.000710 AC: 22 AN: 30976

American (AMR) AF: 0.000187 AC: 2 AN: 10699

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3537

South Asian (SAS) AF: 0.00376 AC: 10 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53201

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.000435 Hom.: 1

Bravo AF: 0.000185

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000407 AC: 49

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Ovarian dysgenesis 2 (2)
1	-	-	Premature ovarian failure 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.15
MVP		0.93
MPC		0.19
ClinPred		0.14	T
GERP RS		4.1
PromoterAI		-0.031	Neutral
Varity_R		0.15
gMVP		0.61
Mutation Taster		=87/13	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: rs104894766; hg19: chrX-50654009; COSMIC: COSV99399454;