rs104894767

Variant names:

• chrX-50915966-G-A
• rs104894767
• NM_005448.2:c.538G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-50915966-G-A
• chrX-50915966-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005448.2(BMP15):​c.538G>A​(p.Ala180Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,209,873 control chromosomes in the GnomAD database, including 87 homozygotes. There are 4,906 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0089 (5 hom., 266 hem., cov: 22)
  • Exomes 𝑓: 0.013 (82 hom. 4640 hem.)
• Consequence: BMP15 NM_005448.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 0.0250

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24070045).
• BP6: Variant X-50915966-G-A is Benign according to our data. Variant chrX-50915966-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11472.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chrX-50915966-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00893 (997/111691) while in subpopulation NFE AF = 0.015 (798/53148). AF 95% confidence interval is 0.0142. There are 5 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP15	NM_005448.2	c.538G>A	p.Ala180Thr	missense_variant	Exon 2 of 2	ENST00000252677.4	NP_005439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP15	ENST00000252677.4	c.538G>A	p.Ala180Thr	missense_variant	Exon 2 of 2	1	NM_005448.2	ENSP00000252677.3

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 997 AN: 111636 Hom.: 5 Cov.: 22

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00376

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.00397

GnomAD2 exomes AF: 0.0100 AC: 1834 AN: 183194 AF XY: 0.00989

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00521

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00751

GnomAD4 exome AF: 0.0133 AC: 14600 AN: 1098182 Hom.: 82 Cov.: 32 AF XY: 0.0128 AC XY: 4640 AN XY: 363546

Gnomad4 AFR exome AF: 0.00186 AC: 49 AN: 26401

Gnomad4 AMR exome AF: 0.00261 AC: 92 AN: 35207

Gnomad4 ASJ exome AF: 0.00547 AC: 106 AN: 19386

Gnomad4 EAS exome AF: 0.0000662 AC: 2 AN: 30206

Gnomad4 SAS exome AF: 0.00436 AC: 236 AN: 54137

Gnomad4 FIN exome AF: 0.0191 AC: 776 AN: 40533

Gnomad4 NFE exome AF: 0.0152 AC: 12778 AN: 842079

Gnomad4 Remaining exome AF: 0.0119 AC: 550 AN: 46096

GnomAD4 genome AF: 0.00893 AC: 997 AN: 111691 Hom.: 5 Cov.: 22 AF XY: 0.00785 AC XY: 266 AN XY: 33889

Gnomad4 AFR AF: 0.00172 AC: 0.00172487 AN: 0.00172487

Gnomad4 AMR AF: 0.00248 AC: 0.00247525 AN: 0.00247525

Gnomad4 ASJ AF: 0.00604 AC: 0.00604458 AN: 0.00604458

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00377 AC: 0.00376932 AN: 0.00376932

Gnomad4 FIN AF: 0.0144 AC: 0.0143968 AN: 0.0143968

Gnomad4 NFE AF: 0.0150 AC: 0.0150147 AN: 0.0150147

Gnomad4 OTH AF: 0.00392 AC: 0.00392157 AN: 0.00392157

Alfa AF: 0.00873 Hom.: 111

Bravo AF: 0.00792

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0187 AC: 54

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.0141 AC: 95

ExAC AF: 0.0103 AC: 1257

EpiCase AF: 0.0155

EpiControl AF: 0.0118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ovarian dysgenesis 2 Uncertain:1 Benign:1

Mar 06, 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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Premature ovarian failure 4 Pathogenic:1

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.10
DANN	Benign	0.74
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.44
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.12	B
Vest4		0.019
MPC		0.022
ClinPred		0.00079	T
GERP RS		-2.5
Varity_R		0.039
gMVP		0.37
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs104894767; hg19: chrX-50658966; COSMIC: COSV53141311;