Variant X-50910971-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_005448.2(BMP15):c.188T>A(p.Leu63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000748 in 1,190,254 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000082 ( 0 hom. 33 hem. )

Consequence

BMP15
NM_005448.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.898

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 Likely_benign. Variant got -4 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=0.07451719).

BS2

High Hemizygotes in GnomAdExome4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2 linkuse as main transcript	c.188T>A	p.Leu63Gln	missense_variant	1/2	ENST00000252677.4	NP_005439.2	O95972

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4 linkuse as main transcript	c.188T>A	p.Leu63Gln	missense_variant	1/2	1	NM_005448.2	ENSP00000252677.3		O95972

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112431

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34593

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000764

AC:

AN:

143919

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

43941

show subpopulations

Gnomad AFR exome

AF:

0.0000980

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000816

AC:

AN:

1077823

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

350581

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

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:

0.000103

Gnomad4 OTH exome

AF:

0.0000221

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112431

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34593

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000298

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.188T>A (p.L63Q) alteration is located in exon 1 (coding exon 1) of the BMP15 gene. This alteration results from a T to A substitution at nucleotide position 188, causing the leucine (L) at amino acid position 63 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.1

DANN

Benign

0.21

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.59

M_CAP

Benign

0.011

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.91

PrimateAI

Benign

0.33

PROVEAN

Benign

1.5

REVEL

Benign

0.15

Sift

Benign

0.50

Sift4G

Benign

0.59

Polyphen

0.010

Vest4

0.19

MVP

0.86

MPC

0.022

ClinPred

0.023

GERP RS

-2.7

Varity_R

0.11

gMVP

0.41

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