7-33905589-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001365308.1(BMPER):c.-25C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,609,696 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 29)
  • Exomes 𝑓: 0.00092 (19 hom.)
• Consequence: BMPER NM_001365308.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.36

Genes affected

BMPER (HGNC:24154): (BMP binding endothelial regulator) This gene encodes a secreted protein that interacts with, and inhibits bone morphogenetic protein (BMP) function. It has been shown to inhibit BMP2- and BMP4-dependent osteoblast differentiation and BMP-dependent differentiation of the chondrogenic cells. Mutations in this gene are associated with a lethal skeletal disorder, diaphanospondylodysostosis. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-33905589-C-A is Benign according to our data. Variant chr7-33905589-C-A is described in ClinVar as [Benign]. Clinvar id is 360095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00932 (1416/151910) while in subpopulation AFR AF= 0.0328 (1358/41376). AF 95% confidence interval is 0.0314. There are 20 homozygotes in gnomad4. There are 653 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPER	NM_001365308.1	c.-25C>A		5_prime_UTR_variant	1/15	ENST00000649409.2
BMPER	NM_001410872.1	c.-25C>A		5_prime_UTR_variant	1/14
BMPER	NM_133468.5	c.-25C>A		5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPER	ENST00000649409.2	c.-25C>A		5_prime_UTR_variant	1/15		NM_001365308.1	P1

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1414 AN: 151806 Hom.: 20 Cov.: 29

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00266 AC: 653 AN: 245746 Hom.: 8 AF XY: 0.00177 AC XY: 237 AN XY: 133660

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000986

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000915 AC: 1334 AN: 1457786 Hom.: 19 Cov.: 32 AF XY: 0.000752 AC XY: 545 AN XY: 725210

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00932 AC: 1416 AN: 151910 Hom.: 20 Cov.: 29 AF XY: 0.00879 AC XY: 653 AN XY: 74268

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00656 Hom.: 1

Bravo AF: 0.0107

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diaphanospondylodysostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75295552; hg19: chr7-33945201;