Genetic Variant NM_005448.2:c.262C>A (chrX-50911045-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005448.2(BMP15):c.262C>A(p.Arg88Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R88C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.90

Publications

0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
46 XX gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BMP15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.262C>A	p.Arg88Ser	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.262C>A	p.Arg88Ser	missense	Exon 1 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26108

American (AMR)

AF:

0.0000296

AC:

AN:

33752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19075

East Asian (EAS)

AF:

0.0000339

AC:

AN:

29489

South Asian (SAS)

AF:

0.00

AC:

AN:

51974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39245

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4027

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835412

Other (OTH)

AF:

0.00

AC:

AN:

45548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

-0.088

MutationAssessor

Uncertain

2.5

PhyloP100

1.9

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.62

MutPred

0.49

Gain of glycosylation at R88 (P = 0.0144)

MVP

0.98

MPC

0.18

ClinPred

0.98

GERP RS

3.9

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.74

gMVP

0.75

Mutation Taster

=87/13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over