rs41308602

chrX-50911091-A-G

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.308A>G(p.Asn103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 1,183,664 control chromosomes in the GnomAD database, including 2,296 homozygotes. There are 27,334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (151 hom., 1764 hem., cov: 24)
  • Exomes 𝑓: 0.073 (2145 hom. 25570 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0570

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=0.0018285215).
• BP6: Variant X-50911091-A-G is Benign according to our data. Variant chrX-50911091-A-G is described in ClinVar as [Benign]. Clinvar id is 136523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP15	NM_005448.2	c.308A>G	p.Asn103Ser	missense_variant	1/2	ENST00000252677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP15	ENST00000252677.4	c.308A>G	p.Asn103Ser	missense_variant	1/2	1	NM_005448.2	P1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 5769 AN: 112834 Hom.: 151 Cov.: 24 AF XY: 0.0505 AC XY: 1765 AN XY: 34978

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.0347

GnomAD3 exomes AF: 0.0571 AC: 7747 AN: 135741 Hom.: 198 AF XY: 0.0612 AC XY: 2594 AN XY: 42363

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0631

Gnomad FIN exome AF: 0.0897

Gnomad NFE exome AF: 0.0804

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0729 AC: 78070 AN: 1070775 Hom.: 2145 Cov.: 33 AF XY: 0.0735 AC XY: 25570 AN XY: 347937

Gnomad4 AFR exome AF: 0.00892

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0000700

Gnomad4 SAS exome AF: 0.0633

Gnomad4 FIN exome AF: 0.0854

Gnomad4 NFE exome AF: 0.0804

Gnomad4 OTH exome AF: 0.0617

GnomAD4 genome AF: 0.0511 AC: 5768 AN: 112889 Hom.: 151 Cov.: 24 AF XY: 0.0503 AC XY: 1764 AN XY: 35043

Gnomad4 AFR AF: 0.00965

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000564

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0768

Gnomad4 OTH AF: 0.0343

Alfa AF: 0.0701 Hom.: 3677

Bravo AF: 0.0470

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0779 AC: 225

ESP6500AA AF: 0.0113 AC: 43

ESP6500EA AF: 0.0800 AC: 535

ExAC AF: 0.0493 AC: 5738

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2014	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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.10
Dann	Benign	0.37
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.12
Sift	Benign	0.71	T
Sift4G	Benign	0.99	T
Polyphen		0.0020	B
Vest4		0.011
MPC		0.021
ClinPred		0.0034	T
GERP RS		0.75
Varity_R		0.028
gMVP		0.14

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: rs41308602; hg19: chrX-50654091; COSMIC: COSV53140249;