chrX-50910806-G-T

Variant names:

• chrX-50910806-G-T
• rs781806618
• NM_005448.2:c.23G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005448.2(BMP15):​c.23G>T​(p.Arg8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,094,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2	c.23G>T	p.Arg8Ile	missense_variant	Exon 1 of 2	ENST00000252677.4	NP_005439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4	c.23G>T	p.Arg8Ile	missense_variant	Exon 1 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000576 AC: 1 AN: 173604 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59074

Gnomad AFR exome AF: 0.00

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: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1094726 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1 AN XY: 360490

Gnomad4 AFR exome AF: 0.00

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: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000113

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23G>T (p.R8I) alteration is located in exon 1 (coding exon 1) of the BMP15 gene. This alteration results from a G to T substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by an isoleucine (I). 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	0.23
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.41	T
Polyphen		0.73	P
Vest4		0.56
MutPred		0.57		Loss of methylation at R8 (P = 0.0496);
MVP		0.95
MPC		0.15
ClinPred		0.38	T
GERP RS		2.3
Varity_R		0.10
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

Other links and lift over

dbSNP: rs781806618; hg19: chrX-50653806; COSMIC: COSV53141164; COSMIC: COSV53141164;