7-33906801-T-C

Variant names:

• chr7-33906801-T-C
• rs542452381
• NM_001365308.1:c.134-17T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001365308.1(BMPER):​c.134-17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,603,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BMPER NM_001365308.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.387
• Publications: 0 publications found

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]

BMPER Gene-Disease associations (from GenCC):

• diaphanospondylodysostosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• ischio-vertebral syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-33906801-T-C is Benign according to our data. Variant chr7-33906801-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445605.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000324 (47/1451214) while in subpopulation EAS AF = 0.00048 (19/39610). AF 95% confidence interval is 0.000313. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365308.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPER	NM_001365308.1	MANE Select	c.134-17T>C		intron	N/A	NP_001352237.1
	BMPER	NM_133468.5		c.134-17T>C		intron	N/A	NP_597725.1
	BMPER	NM_001410872.1		c.134-17T>C		intron	N/A	NP_001397801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPER	ENST00000649409.2	MANE Select	c.134-17T>C		intron	N/A	ENSP00000497748.1
	BMPER	ENST00000297161.6	TSL:1	c.134-17T>C		intron	N/A	ENSP00000297161.2
	BMPER	ENST00000649771.1		n.-88T>C		non_coding_transcript_exon	Exon 1 of 14	ENSP00000497314.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251146 AF XY: 0.0000663

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000324 AC: 47 AN: 1451214 Hom.: 0 Cov.: 30 AF XY: 0.0000387 AC XY: 28 AN XY: 722650

African (AFR) AF: 0.000151 AC: 5 AN: 33212

American (AMR) AF: 0.000179 AC: 8 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.000480 AC: 19 AN: 39610

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1102612

Other (OTH) AF: 0.0000333 AC: 2 AN: 60004

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74450

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.40
PhyloP100		0.39
PromoterAI		0.0061	Neutral

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: rs542452381; hg19: chr7-33946413; COSMIC: COSV51819967;