X-50911091-A-G

Position:

chrX-50911091-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005448.2(BMP15):c.308A>G(p.Asn103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 1,183,664 control chromosomes in the GnomAD database, including 2,296 homozygotes. There are 27,334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 151 hom., 1764 hem., cov: 24)

Exomes 𝑓: 0.073 ( 2145 hom. 25570 hem. )

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0570

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 Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0018285215).

BP6

Variant X-50911091-A-G is Benign according to our data. Variant chrX-50911091-A-G is described in ClinVar as [Benign]. Clinvar id is 136523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2 linkuse as main transcript	c.308A>G	p.Asn103Ser	missense_variant	1/2	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.308A>G	p.Asn103Ser	missense_variant	1/2	1	NM_005448.2	ENSP00000252677	P1

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

5769

AN:

112834

Hom.:

151

Cov.:

AF XY:

0.0505

AC XY:

1765

AN XY:

34978

show subpopulations

Gnomad AFR

AF:

0.00967

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.000563

Gnomad SAS

AF:

0.0563

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.0417

Gnomad NFE

AF:

0.0768

Gnomad OTH

AF:

0.0347

GnomAD3 exomes

AF:

0.0571

AC:

7747

AN:

135741

Hom.:

198

AF XY:

0.0612

AC XY:

2594

AN XY:

42363

show subpopulations

Gnomad AFR exome

AF:

0.00962

Gnomad AMR exome

AF:

0.0260

Gnomad ASJ exome

AF:

0.0468

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0631

Gnomad FIN exome

AF:

0.0897

Gnomad NFE exome

AF:

0.0804

Gnomad OTH exome

AF:

0.0623

GnomAD4 exome

AF:

0.0729

AC:

78070

AN:

1070775

Hom.:

2145

Cov.:

AF XY:

0.0735

AC XY:

25570

AN XY:

347937

show subpopulations

Gnomad4 AFR exome

AF:

0.00892

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0458

Gnomad4 EAS exome

AF:

0.0000700

Gnomad4 SAS exome

AF:

0.0633

Gnomad4 FIN exome

AF:

0.0854

Gnomad4 NFE exome

AF:

0.0804

Gnomad4 OTH exome

AF:

0.0617

GnomAD4 genome

AF:

0.0511

AC:

5768

AN:

112889

Hom.:

151

Cov.:

AF XY:

0.0503

AC XY:

1764

AN XY:

35043

show subpopulations

Gnomad4 AFR

AF:

0.00965

Gnomad4 AMR

AF:

0.0433

Gnomad4 ASJ

AF:

0.0366

Gnomad4 EAS

AF:

0.000564

Gnomad4 SAS

AF:

0.0564

Gnomad4 FIN

AF:

0.0760

Gnomad4 NFE

AF:

0.0768

Gnomad4 OTH

AF:

0.0343

Alfa

AF:

0.0701

Hom.:

3677

Bravo

AF:

0.0470

TwinsUK

AF:

0.0779

AC:

289

ALSPAC

AF:

0.0779

AC:

225

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0800

AC:

535

ExAC

AF:

0.0493

AC:

5738

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ovarian dysgenesis 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.10

DANN

Benign

0.37

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.29

REVEL

Benign

0.12

Sift

Benign

0.71

Sift4G

Benign

0.99

Polyphen

0.0020

Vest4

0.011

MPC

0.021

ClinPred

0.0034

GERP RS

0.75

Varity_R

0.028

gMVP

0.14

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