Genetic Variant NM_005448.2:c.538G>T (chrX-50915966-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005448.2(BMP15):c.538G>T(p.Ala180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,209,883 control chromosomes in the GnomAD database, including 1 homozygotes. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A180T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00010 ( 1 hom. 60 hem. )

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0482015).

BS2

High AC in GnomAd4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2 link	c.538G>T	p.Ala180Ser	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>T	p.Ala180Ser	missense_variant	Exon 2 of 2	1	NM_005448.2	ENSP00000252677.3		O95972

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

111638

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000229

AC:

AN:

183194

AF XY:

0.000354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

114

AN:

1098190

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

AN XY:

363550

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00190

AC:

103

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842087

Other (OTH)

AF:

0.000195

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000985

AC:

AN:

111693

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33889

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30727

American (AMR)

AF:

0.00

AC:

AN:

10504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00415

AC:

AN:

2653

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6043

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.00

Hom.:

111

Bravo

AF:

0.0000340

ExAC

AF:

0.000305

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.037

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.20

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

PhyloP100

0.025

PrimateAI

Benign

0.24

PROVEAN

Benign

0.17

REVEL

Benign

0.17

Sift

Benign

0.42

Sift4G

Benign

0.56

Polyphen

0.16

Vest4

0.046

MutPred

0.45

Gain of disorder (P = 0.0093);

MVP

0.81

MPC

0.024

ClinPred

0.029

GERP RS

-2.5

Varity_R

0.042

gMVP

0.35

Mutation Taster

=93/7

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

Computational scores

Splicing

Publications

Other links and lift over