NM_005448.2:c.852C>T

Variant names:

• chrX-50916280-C-T
• rs17003221
• NM_005448.2:c.852C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005448.2(BMP15):​c.852C>T​(p.Ser284Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,204,453 control chromosomes in the GnomAD database, including 4,695 homozygotes. There are 12,892 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2306 hom., 4061 hem., cov: 22)
  • Exomes 𝑓: 0.024 (2389 hom. 8831 hem.)
• Consequence: BMP15 NM_005448.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.249
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-50916280-C-T is Benign according to our data. Variant chrX-50916280-C-T is described in ClinVar as Benign. ClinVar VariationId is 259777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.249 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 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.852C>T	p.Ser284Ser	synonymous	Exon 2 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.852C>T	p.Ser284Ser	synonymous	Exon 2 of 2	ENSP00000252677.3	O95972

Frequencies

GnomAD3 genomes AF: 0.136 AC: 15016 AN: 110635 Hom.: 2307 Cov.: 22

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0194

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.0910

Gnomad FIN AF: 0.000335

Gnomad MID AF: 0.0591

Gnomad NFE AF: 0.00477

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0581 AC: 10426 AN: 179550 AF XY: 0.0490

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.0652

Gnomad FIN exome AF: 0.0000635

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0237 AC: 25942 AN: 1093762 Hom.: 2389 Cov.: 32 AF XY: 0.0246 AC XY: 8831 AN XY: 359690

African (AFR) AF: 0.449 AC: 11817 AN: 26315

American (AMR) AF: 0.0454 AC: 1593 AN: 35053

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 363 AN: 19159

East Asian (EAS) AF: 0.0699 AC: 2106 AN: 30133

South Asian (SAS) AF: 0.100 AC: 5348 AN: 53363

European-Finnish (FIN) AF: 0.000124 AC: 5 AN: 40423

Middle Eastern (MID) AF: 0.0506 AC: 208 AN: 4111

European-Non Finnish (NFE) AF: 0.00293 AC: 2462 AN: 839311

Other (OTH) AF: 0.0445 AC: 2040 AN: 45894

GnomAD4 genome AF: 0.136 AC: 15023 AN: 110691 Hom.: 2306 Cov.: 22 AF XY: 0.123 AC XY: 4061 AN XY: 32967

African (AFR) AF: 0.446 AC: 13462 AN: 30156

American (AMR) AF: 0.0603 AC: 628 AN: 10406

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 51 AN: 2632

East Asian (EAS) AF: 0.0647 AC: 227 AN: 3509

South Asian (SAS) AF: 0.0897 AC: 230 AN: 2564

European-Finnish (FIN) AF: 0.000335 AC: 2 AN: 5977

Middle Eastern (MID) AF: 0.0599 AC: 13 AN: 217

European-Non Finnish (NFE) AF: 0.00477 AC: 253 AN: 53025

Other (OTH) AF: 0.103 AC: 157 AN: 1517

Alfa AF: 0.0715 Hom.: 3881

Bravo AF: 0.155

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	-0.90
CADD	Benign	0.25
DANN	Benign	0.40
PhyloP100		-0.25
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: rs17003221; hg19: chrX-50659280; COSMIC: COSV53139908;