X-50915871-T-C

Position:

chrX-50915871-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000252677.4(BMP15):c.443T>C(p.Leu148Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,208,918 control chromosomes in the GnomAD database, including 14 homozygotes. There are 572 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 4 hom., 211 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 10 hom. 361 hem. )

Consequence

BMP15
ENST00000252677.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.64

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012938619).

BP6

Variant X-50915871-T-C is Benign according to our data. Variant chrX-50915871-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 368538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50915871-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00764 (849/111182) while in subpopulation AFR AF= 0.0245 (749/30577). AF 95% confidence interval is 0.023. There are 4 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2 linkuse as main transcript	c.443T>C	p.Leu148Pro	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.443T>C	p.Leu148Pro	missense_variant	2/2	1	NM_005448.2	ENSP00000252677	P1

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

850

AN:

111128

Hom.:

Cov.:

AF XY:

0.00630

AC XY:

210

AN XY:

33340

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00384

Gnomad ASJ

AF:

0.00946

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000491

Gnomad OTH

AF:

0.00598

GnomAD3 exomes

AF:

0.00317

AC:

580

AN:

182710

Hom.:

AF XY:

0.00215

AC XY:

145

AN XY:

67288

show subpopulations

Gnomad AFR exome

AF:

0.0270

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000515

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.00117

AC:

1287

AN:

1097736

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

361

AN XY:

363124

show subpopulations

Gnomad4 AFR exome

AF:

0.0261

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.00924

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000214

Gnomad4 OTH exome

AF:

0.00228

GnomAD4 genome

AF:

0.00764

AC:

849

AN:

111182

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

211

AN XY:

33404

show subpopulations

Gnomad4 AFR

AF:

0.0245

Gnomad4 AMR

AF:

0.00383

Gnomad4 ASJ

AF:

0.00946

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000491

Gnomad4 OTH

AF:

0.00590

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00973

ESP6500AA

AF:

0.0243

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.00295

AC:

358

EpiCase

AF:

0.000763

EpiControl

AF:

0.000714

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	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:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.71

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.041

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

0.91

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.70

MVP

0.92

MPC

0.20

ClinPred

0.045

GERP RS

5.4

Varity_R

0.87

gMVP

0.84

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