chrX-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: AD, XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005448.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	NM_005448.2	MANE Select	c.-9C>G		5_prime_UTR	Exon 1 of 2	NP_005439.2	O95972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP15	ENST00000252677.4	TSL:1 MANE Select	c.-9C>G		5_prime_UTR	Exon 1 of 2	ENSP00000252677.3	O95972

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Ovarian dysgenesis 2 (1)

Computational scores

Source: dbNSFP v4.9

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;