rs104894763

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3

Conservation

PhyloP100: 2.05

Publications

19 publications found

Variant links:

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

BMP15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2 link	c.202C>T	p.Arg68Trp	missense_variant	Exon 1 of 2	ENST00000252677.4	NP_005439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4 link	c.202C>T	p.Arg68Trp	missense_variant	Exon 1 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

112256

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00114

AC XY:

400

AN XY:

350677

show subpopulations

African (AFR)

AF:

0.000347

AC:

AN:

25902

American (AMR)

AF:

0.000432

AC:

AN:

32381

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18991

East Asian (EAS)

AF:

0.0000344

AC:

AN:

29050

South Asian (SAS)

AF:

0.000194

AC:

AN:

51455

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39165

Middle Eastern (MID)

AF:

0.000248

AC:

AN:

4026

European-Non Finnish (NFE)

AF:

0.00140

AC:

1166

AN:

831535

Other (OTH)

AF:

0.00110

AC:

AN:

45332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000623

AC:

AN:

112307

Hom.:

Cov.:

AF XY:

0.000638

AC XY:

AN XY:

34489

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

30978

American (AMR)

AF:

0.000562

AC:

AN:

10672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6145

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

53213

Other (OTH)

AF:

0.00130

AC:

AN:

1537

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000535

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BMP15: PS4:Moderate, PS3:Supporting -

Sep 14, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with premature ovarian insufficiency referred for genetic testing at GeneDx and in published literature (Di Pasquale et al., 2006); Identified in a patient with polycystic ovary syndrome and normal serum androgen levels in published literature (Crespo et al., 2022); Published functional studies demonstrate a reduction of mature protein production and decreased synergy with GDF9, however, the biological significance of these effects is uncertain (Rossetti et al., 2009; Patio et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35898701, 28359091, 19377476, 16464940, 19263482) -

Premature ovarian failure 4

Pathogenic:1

May 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Ovarian dysgenesis 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BMP15-related disorder

Benign:1

Aug 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.2

PhyloP100

2.0

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.15

MVP

0.97

MPC

0.16

ClinPred

0.082

GERP RS

1.8

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.19

gMVP

0.67

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over