NM_005448.2:c.462delC

Variant names:

• chrX-50915887-GC-G
• rs1923115287
• NM_005448.2:c.462delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005448.2(BMP15):​c.462delC​(p.Trp155GlyfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BMP15 NM_005448.2 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.414
• 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: AD, XL 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 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-50915887-GC-G is Pathogenic according to our data. Variant chrX-50915887-GC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 973166.Status of the report is no_assertion_criteria_provided, 0 stars.

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.462delC	p.Trp155GlyfsTer22	frameshift	Exon 2 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.462delC	p.Trp155GlyfsTer22	frameshift	Exon 2 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ovarian dysgenesis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=41/159	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1923115287; hg19: chrX-50658887;