X-50910798-T-A

Variant names:

• chrX-50910798-T-A
• NM_005448.2:c.15T>A
• BMP15 p.Ser5Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005448.2(BMP15):​c.15T>A​(p.Ser5Arg) 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 pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ovarian dysgenesis 2

  Inheritance: XL, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005448.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	NM_005448.2	MANE Select	c.15T>A	p.Ser5Arg	missense	Exon 1 of 2	NP_005439.2	O95972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	ENST00000252677.4	TSL:1 MANE Select	c.15T>A	p.Ser5Arg	missense	Exon 1 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.39
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.060	T
PromoterAI		0.0068	Neutral
Varity_R		0.17
gMVP		0.36
Mutation Taster		=85/15	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-50653798;