X-50910775-C-G

Variant names:

• chrX-50910775-C-G
• rs3810682
• NM_005448.2:c.-9C>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.-9C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,198,204 control chromosomes in the GnomAD database, including 18,782 homozygotes. There are 80,825 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1566 hom., 6090 hem., cov: 23)
  • Exomes 𝑓: 0.21 (17216 hom. 74735 hem.)
• Consequence: BMP15 NM_005448.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.25
• Publications: 38 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 (BayesDel_noAF=-0.89).
• BP6: Variant X-50910775-C-G is Benign according to our data. Variant chrX-50910775-C-G is described in ClinVar as Benign. ClinVar VariationId is 136522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2	c.-9C>G		5_prime_UTR_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.-9C>G		5_prime_UTR_variant	Exon 1 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 21086 AN: 111376 Hom.: 1567 Cov.: 23

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.162 AC: 26645 AN: 163988 AF XY: 0.154

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0845

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0295

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.211 AC: 229503 AN: 1086775 Hom.: 17216 Cov.: 31 AF XY: 0.211 AC XY: 74735 AN XY: 354563

African (AFR) AF: 0.170 AC: 4453 AN: 26177

American (AMR) AF: 0.0905 AC: 3115 AN: 34405

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 4351 AN: 19213

East Asian (EAS) AF: 0.0525 AC: 1576 AN: 30004

South Asian (SAS) AF: 0.188 AC: 9892 AN: 52681

European-Finnish (FIN) AF: 0.183 AC: 7340 AN: 40010

Middle Eastern (MID) AF: 0.247 AC: 1018 AN: 4125

European-Non Finnish (NFE) AF: 0.226 AC: 188428 AN: 834482

Other (OTH) AF: 0.204 AC: 9330 AN: 45678

GnomAD4 genome AF: 0.189 AC: 21089 AN: 111429 Hom.: 1566 Cov.: 23 AF XY: 0.181 AC XY: 6090 AN XY: 33661

African (AFR) AF: 0.160 AC: 4914 AN: 30661

American (AMR) AF: 0.137 AC: 1447 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 567 AN: 2640

East Asian (EAS) AF: 0.0394 AC: 139 AN: 3529

South Asian (SAS) AF: 0.176 AC: 464 AN: 2634

European-Finnish (FIN) AF: 0.168 AC: 1015 AN: 6026

Middle Eastern (MID) AF: 0.188 AC: 41 AN: 218

European-Non Finnish (NFE) AF: 0.228 AC: 12080 AN: 52968

Other (OTH) AF: 0.159 AC: 241 AN: 1515

Alfa AF: 0.216 Hom.: 5885

Bravo AF: 0.184

ClinVar

Significance: Benign

Submissions summary: Benign:4

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:1

Jan 12, 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
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-1.3
PromoterAI		-0.019	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3810682; hg19: chrX-50653775; COSMIC: COSV53141027;