rs104894763

Variant names:

• chrX-50910985-C-T
• rs104894763
• NM_005448.2:c.202C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4 BP6 BS2

The NM_005448.2(BMP15):​c.202C>T​(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,190,144 control chromosomes in the GnomAD database, including 1 homozygotes. There are 422 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., 22 hem., cov: 24)
  • Exomes 𝑓: 0.0012 (1 hom. 400 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: 2.05

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 -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=0.3806206).
• BP6: Variant X-50910985-C-T is Benign according to our data. Variant chrX-50910985-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11474.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chrX-50910985-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2	c.202C>T	p.Arg68Trp	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.202C>T	p.Arg68Trp	missense_variant	Exon 1 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 70 AN: 112256 Hom.: 0 Cov.: 24 AF XY: 0.000639 AC XY: 22 AN XY: 34428

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000563

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: 0.00109

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000700 AC: 101 AN: 144352 Hom.: 0 AF XY: 0.000681 AC XY: 30 AN XY: 44062

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.000254

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000257

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.000263

GnomAD4 exome AF: 0.00116 AC: 1251 AN: 1077837 Hom.: 1 Cov.: 33 AF XY: 0.00114 AC XY: 400 AN XY: 350677

Gnomad4 AFR exome AF: 0.000347

Gnomad4 AMR exome AF: 0.000432

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000344

Gnomad4 SAS exome AF: 0.000194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000623 AC: 70 AN: 112307 Hom.: 0 Cov.: 24 AF XY: 0.000638 AC XY: 22 AN XY: 34489

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000943 Hom.: 38

Bravo AF: 0.000763

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00178 AC: 12

ExAC AF: 0.000535 AC: 64

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with premature ovarian insufficiency referred for genetic testing at GeneDx and in published literature (Di Pasquale et al., 2006); Identified in a patient with polycystic ovary syndrome and normal serum androgen levels in published literature (Crespo et al., 2022); Published functional studies demonstrate a reduction of mature protein production and decreased synergy with GDF9, however, the biological significance of these effects is uncertain (Rossetti et al., 2009; Patio et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35898701, 28359091, 19377476, 16464940, 19263482) -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMP15: PS4:Moderate, PS3:Supporting -

Premature ovarian failure 4 Pathogenic:1

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ovarian dysgenesis 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BMP15-related disorder Benign:1

Aug 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.15
MVP		0.97
MPC		0.16
ClinPred		0.082	T
GERP RS		1.8
Varity_R		0.19
gMVP		0.67

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: rs104894763; hg19: chrX-50653985;