rs104894767

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_005448.2(BMP15):c.538G>A(p.Ala180Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,209,873 control chromosomes in the GnomAD database, including 87 homozygotes. There are 4,906 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0089 ( 5 hom., 266 hem., cov: 22)

Exomes 𝑓: 0.013 ( 82 hom. 4640 hem. )

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0250

Publications

29 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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24070045).

BP6

Variant X-50915966-G-A is Benign according to our data. Variant chrX-50915966-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11472.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00893 (997/111691) while in subpopulation NFE AF = 0.015 (798/53148). AF 95% confidence interval is 0.0142. There are 5 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 997 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2 link	c.538G>A	p.Ala180Thr	missense_variant	Exon 2 of 2	ENST00000252677.4	NP_005439.2	O95972

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4 link	c.538G>A	p.Ala180Thr	missense_variant	Exon 2 of 2	1	NM_005448.2	ENSP00000252677.3		O95972

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

997

AN:

111636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00248

Gnomad ASJ

AF:

0.00604

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00376

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.00397

GnomAD2 exomes

AF:

0.0100

AC:

1834

AN:

183194

AF XY:

0.00989

show subpopulations

Gnomad AFR exome

AF:

0.00190

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00521

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.00751

GnomAD4 exome

AF:

0.0133

AC:

14600

AN:

1098182

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

4640

AN XY:

363546

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

26401

American (AMR)

AF:

0.00261

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

106

AN:

19386

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30206

South Asian (SAS)

AF:

0.00436

AC:

236

AN:

54137

European-Finnish (FIN)

AF:

0.0191

AC:

776

AN:

40533

Middle Eastern (MID)

AF:

0.00266

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0152

AC:

12778

AN:

842079

Other (OTH)

AF:

0.0119

AC:

550

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

619

1237

1856

2474

3093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.00893

AC:

997

AN:

111691

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

266

AN XY:

33889

show subpopulations

African (AFR)

AF:

0.00172

AC:

AN:

30727

American (AMR)

AF:

0.00248

AC:

AN:

10504

Ashkenazi Jewish (ASJ)

AF:

0.00604

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00377

AC:

AN:

2653

European-Finnish (FIN)

AF:

0.0144

AC:

AN:

6043

Middle Eastern (MID)

AF:

0.00465

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0150

AC:

798

AN:

53148

Other (OTH)

AF:

0.00392

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

118

157

196

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:

0.00873

Hom.:

111

Bravo

AF:

0.00792

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.0141

AC:

ExAC

AF:

0.0103

AC:

1257

EpiCase

AF:

0.0155

EpiControl

AF:

0.0118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ovarian dysgenesis 2

Uncertain:1Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Premature ovarian failure 4

Pathogenic:1

May 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

0.10

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.62

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.5

PhyloP100

0.025

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.010

REVEL

Uncertain

0.44

Sift

Benign

0.27

Sift4G

Benign

0.40

Polyphen

0.12

Vest4

0.019

MPC

0.022

ClinPred

0.00079

GERP RS

-2.5

Varity_R

0.039

gMVP

0.37

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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