7-33905662-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365308.1(BMPER):c.49C>T(p.Arg17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: BMPER NM_001365308.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0590

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3309337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPER	NM_001365308.1	c.49C>T	p.Arg17Cys	missense_variant	1/15	ENST00000649409.2
BMPER	NM_133468.5	c.49C>T	p.Arg17Cys	missense_variant	2/16
BMPER	NM_001410872.1	c.49C>T	p.Arg17Cys	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPER	ENST00000649409.2	c.49C>T	p.Arg17Cys	missense_variant	1/15		NM_001365308.1	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.49C>T (p.R17C) alteration is located in exon 1 (coding exon 1) of the BMPER gene. This alteration results from a C to T substitution at nucleotide position 49, causing the arginine (R) at amino acid position 17 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N;.;.;.
MutationTaster	Benign	0.60	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.33	N;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.032	D;.;.;.;.;.
Sift4G	Benign	0.081	T;.;.;.;.;.
Polyphen		0.57	P;.;P;.;.;.
Vest4		0.32
MutPred		0.61		Loss of phosphorylation at S18 (P = 0.1405);Loss of phosphorylation at S18 (P = 0.1405);Loss of phosphorylation at S18 (P = 0.1405);Loss of phosphorylation at S18 (P = 0.1405);Loss of phosphorylation at S18 (P = 0.1405);Loss of phosphorylation at S18 (P = 0.1405);
MVP		0.61
MPC		0.33
ClinPred		0.65	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.77

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: rs753940001; hg19: chr7-33945274;