X-50910796-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005448.2(BMP15):c.13A>C(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,205,757 control chromosomes in the GnomAD database, including 295 homozygotes. There are 1,930 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (163 hom., 990 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (132 hom. 940 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.127

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033066273).
• BP6: Variant X-50910796-A-C is Benign according to our data. Variant chrX-50910796-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 259774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.13A>C	p.Ser5Arg	missense_variant	1/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.13A>C	p.Ser5Arg	missense_variant	1/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 3546 AN: 112069 Hom.: 163 Cov.: 23 AF XY: 0.0290 AC XY: 991 AN XY: 34219

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000746

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.00928 AC: 1590 AN: 171381 Hom.: 75 AF XY: 0.00533 AC XY: 305 AN XY: 57273

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00560

Gnomad ASJ exome AF: 0.000960

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00333 AC: 3644 AN: 1093637 Hom.: 132 Cov.: 32 AF XY: 0.00261 AC XY: 940 AN XY: 359625

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00634

Gnomad4 ASJ exome AF: 0.000622

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000691

Gnomad4 OTH exome AF: 0.00784

GnomAD4 genome AF: 0.0316 AC: 3546 AN: 112120 Hom.: 163 Cov.: 23 AF XY: 0.0289 AC XY: 990 AN XY: 34280

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.0273

Alfa AF: 0.00323 Hom.: 87

Bravo AF: 0.0366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.116 AC: 443

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0102 AC: 1239

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ovarian dysgenesis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.060	T
Polyphen		0.84	P
Vest4		0.76
MutPred		0.83		Gain of MoRF binding (P = 5e-04);
MPC		0.040
ClinPred		0.018	T
GERP RS		1.2
Varity_R		0.18
gMVP		0.36

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: rs113099187; hg19: chrX-50653796;