X-50915871-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005448.2(BMP15):c.443T>C(p.Leu148Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,208,918 control chromosomes in the GnomAD database, including 14 homozygotes. There are 572 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., 211 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (10 hom. 361 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.64

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=0.012938619).
• BP6: Variant X-50915871-T-C is Benign according to our data. Variant chrX-50915871-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 368538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50915871-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00764 (849/111182) while in subpopulation AFR AF= 0.0245 (749/30577). AF 95% confidence interval is 0.023. There are 4 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.443T>C	p.Leu148Pro	missense_variant	2/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.443T>C	p.Leu148Pro	missense_variant	2/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 850 AN: 111128 Hom.: 4 Cov.: 22 AF XY: 0.00630 AC XY: 210 AN XY: 33340

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00384

Gnomad ASJ AF: 0.00946

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000491

Gnomad OTH AF: 0.00598

GnomAD3 exomes AF: 0.00317 AC: 580 AN: 182710 Hom.: 1 AF XY: 0.00215 AC XY: 145 AN XY: 67288

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00117 AC: 1287 AN: 1097736 Hom.: 10 Cov.: 32 AF XY: 0.000994 AC XY: 361 AN XY: 363124

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00924

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00764 AC: 849 AN: 111182 Hom.: 4 Cov.: 22 AF XY: 0.00632 AC XY: 211 AN XY: 33404

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00383

Gnomad4 ASJ AF: 0.00946

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000491

Gnomad4 OTH AF: 0.00590

Alfa AF: 0.00199 Hom.: 71

Bravo AF: 0.00973

ESP6500AA AF: 0.0243 AC: 93

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.00295 AC: 358

EpiCase AF: 0.000763

EpiControl AF: 0.000714

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	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. -

Ovarian dysgenesis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.041	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.92
MPC		0.20
ClinPred		0.045	T
GERP RS		5.4
Varity_R		0.87
gMVP		0.84

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: rs114823607; hg19: chrX-50658871;