X-50915966-G-A

Position:

chrX-50915966-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The ENST00000252677.4(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. 13/19 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
ENST00000252677.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0250

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 11472.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chrX-50915966-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2 linkuse as main transcript	c.538G>A	p.Ala180Thr	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.538G>A	p.Ala180Thr	missense_variant	2/2	1	NM_005448.2	ENSP00000252677	P1

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

997

AN:

111636

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

266

AN XY:

33824

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

GnomAD3 exomes

AF:

0.0100

AC:

1834

AN:

183194

Hom.:

AF XY:

0.00989

AC XY:

670

AN XY:

67714

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 SAS exome

AF:

0.00388

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

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.00261

Gnomad4 ASJ exome

AF:

0.00547

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.0152

Gnomad4 OTH exome

AF:

0.0119

GnomAD4 genome

AF:

0.00893

AC:

997

AN:

111691

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

266

AN XY:

33889

show subpopulations

Gnomad4 AFR

AF:

0.00172

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00604

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00377

Gnomad4 FIN

AF:

0.0144

Gnomad4 NFE

AF:

0.0150

Gnomad4 OTH

AF:

0.00392

Alfa

AF:

0.00980

Hom.:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

Premature ovarian failure 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

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

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

MutationTaster

Benign

1.6e-11

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

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