Variant chrX-50916132-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_005448.2(BMP15):c.704A>G(p.Tyr235Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 4.64

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a propeptide (size 248) in uniprot entity BMP15_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_005448.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant X-50916132-A-G is Pathogenic according to our data. Variant chrX-50916132-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11470.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2 linkuse as main transcript	c.704A>G	p.Tyr235Cys	missense_variant	2/2	ENST00000252677.4	NP_005439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4 linkuse as main transcript	c.704A>G	p.Tyr235Cys	missense_variant	2/2	1	NM_005448.2	ENSP00000252677	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000182

AC:

AN:

1098229

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363587

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000237

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ovarian dysgenesis 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -
Pathogenic, no assertion criteria provided	research	Lab of Endocrine and Metabolic Research, Istituto Auxologico Italiano	Dec 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.68

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-8.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.015

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.81

MutPred

0.80

Loss of stability (P = 0.0404);

MVP

0.89

MPC

0.19

ClinPred

0.94

GERP RS

4.4

Varity_R

0.33

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over