rs41308602

Variant names:

• chrX-50911091-A-G
• rs41308602
• NM_005448.2:c.308A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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:5
• Conservation: PhyloP100: -0.0570
• Publications: 18 publications found

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]

BMP15 Gene-Disease associations (from GenCC):

• ovarian dysgenesis 2

  Inheritance: XL, AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
BMP15	NM_005448.2	c.308A>G	p.Asn103Ser	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.308A>G	p.Asn103Ser	missense_variant	Exon 1 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 5769 AN: 112834 Hom.: 151 Cov.: 24

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

GnomAD2 exomes AF: 0.0571 AC: 7747 AN: 135741 AF XY: 0.0612

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 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

African (AFR) AF: 0.00892 AC: 229 AN: 25682

American (AMR) AF: 0.0263 AC: 832 AN: 31598

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 863 AN: 18860

East Asian (EAS) AF: 0.0000700 AC: 2 AN: 28574

South Asian (SAS) AF: 0.0633 AC: 3218 AN: 50814

European-Finnish (FIN) AF: 0.0854 AC: 3258 AN: 38162

Middle Eastern (MID) AF: 0.0685 AC: 262 AN: 3825

European-Non Finnish (NFE) AF: 0.0804 AC: 66629 AN: 828244

Other (OTH) AF: 0.0617 AC: 2777 AN: 45016

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

African (AFR) AF: 0.00965 AC: 301 AN: 31202

American (AMR) AF: 0.0433 AC: 468 AN: 10811

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 97 AN: 2652

East Asian (EAS) AF: 0.000564 AC: 2 AN: 3545

South Asian (SAS) AF: 0.0564 AC: 154 AN: 2729

European-Finnish (FIN) AF: 0.0760 AC: 474 AN: 6236

Middle Eastern (MID) AF: 0.0457 AC: 10 AN: 219

European-Non Finnish (NFE) AF: 0.0768 AC: 4093 AN: 53270

Other (OTH) AF: 0.0343 AC: 53 AN: 1547

Alfa AF: 0.0661 Hom.: 3757

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		-0.057
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
PromoterAI		-0.035	Neutral
Varity_R		0.028
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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