7-33905148-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000297161.6(BMPER):c.-141+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 194,592 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (139 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (3 hom.)
• Consequence: BMPER ENST00000297161.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00007519
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.540

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-33905148-A-G is Benign according to our data. Variant chr7-33905148-A-G is described in ClinVar as [Benign]. Clinvar id is 360092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPER	NM_133468.5	c.-141+4A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPER	ENST00000297161.6	c.-141+4A>G		splice_donor_region_variant, intron_variant		1		P1
BMPER	ENST00000436222.6	n.235+606A>G		intron_variant, non_coding_transcript_variant		5
BMPER	ENST00000448280.5	n.234+4A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4217 AN: 151824 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.00893 AC: 381 AN: 42654 Hom.: 3 Cov.: 0 AF XY: 0.0104 AC XY: 231 AN XY: 22172

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.00868

Gnomad4 EAS exome AF: 0.0407

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00583

GnomAD4 genome AF: 0.0278 AC: 4230 AN: 151938 Hom.: 139 Cov.: 32 AF XY: 0.0276 AC XY: 2054 AN XY: 74294

Gnomad4 AFR AF: 0.0698

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.0595

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00171

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0178 Hom.: 8

Bravo AF: 0.0330

Asia WGS AF: 0.0460 AC: 158 AN: 3474

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	-0.66
Cadd	Benign	11
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs113711026; hg19: chr7-33944760;