X-50911009-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5 PP5 BP4 BS2

The NM_005448.2(BMP15):c.226C>T(p.Arg76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,193,726 control chromosomes in the GnomAD database, including 1 homozygotes. There are 114 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00016 (1 hom. 94 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.51

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant X-50911009-C-T is Pathogenic according to our data. Variant chrX-50911009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11471.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11782113).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.226C>T	p.Arg76Cys	missense_variant	1/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.226C>T	p.Arg76Cys	missense_variant	1/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 36 AN: 112258 Hom.: 0 Cov.: 24 AF XY: 0.000581 AC XY: 20 AN XY: 34438

Gnomad AFR AF: 0.000712

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000413 AC: 62 AN: 150151 Hom.: 0 AF XY: 0.000699 AC XY: 32 AN XY: 45781

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000862

Gnomad SAS exome AF: 0.00354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000258

GnomAD4 exome AF: 0.000164 AC: 177 AN: 1081412 Hom.: 1 Cov.: 33 AF XY: 0.000267 AC XY: 94 AN XY: 352434

Gnomad4 AFR exome AF: 0.000500

Gnomad4 AMR exome AF: 0.0000301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000342

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000600

Gnomad4 OTH exome AF: 0.000176

GnomAD4 genome AF: 0.000321 AC: 36 AN: 112314 Hom.: 0 Cov.: 24 AF XY: 0.000580 AC XY: 20 AN XY: 34504

Gnomad4 AFR AF: 0.000710

Gnomad4 AMR AF: 0.000187

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.00376

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 1

Bravo AF: 0.000185

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000407 AC: 49

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ovarian dysgenesis 2 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 12, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Premature ovarian failure 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.0000082	A
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.15
MVP		0.93
MPC		0.19
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.61

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: rs104894766; hg19: chrX-50654009; COSMIC: COSV99399454;