X-50915957-A-T

Position:

• chrX-50915957-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM2 BP4_Strong BP6_Moderate

The NM_005448.2(BMP15):​c.529A>T​(p.Met177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.738

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.05692348).
• BP6: Variant X-50915957-A-T is Benign according to our data. Variant chrX-50915957-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2493163.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP15	NM_005448.2	c.529A>T	p.Met177Leu	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	c.529A>T	p.Met177Leu	missense_variant	2/2	1	NM_005448.2	ENSP00000252677	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.039
DANN	Benign	0.32
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.060	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.058
MutPred		0.38		Loss of catalytic residue at M177 (P = 0.0849);
MVP		0.56
MPC		0.021
ClinPred		0.024	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-50658957;