rs1554300601

Positions:

• chr7-33970336-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001365308.1(BMPER):​c.410T>A​(p.Val137Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPER NM_001365308.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.50

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• PP5: Variant 7-33970336-T-A is Pathogenic according to our data. Variant chr7-33970336-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559441.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPER	NM_001365308.1	c.410T>A	p.Val137Asp	missense_variant	5/15	ENST00000649409.2
BMPER	NM_133468.5	c.410T>A	p.Val137Asp	missense_variant	6/16
BMPER	NM_001410872.1	c.410T>A	p.Val137Asp	missense_variant	5/14
BMPER	XM_047419939.1	c.-145T>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPER	ENST00000649409.2	c.410T>A	p.Val137Asp	missense_variant	5/15		NM_001365308.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Diaphanospondylodysostosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 26, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	The Danek Gertner Institute of Human Genetics, Sheba Medical Center	Apr 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T;.;T;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.
Polyphen		0.98	D;.;D;.;.;.;.
Vest4		0.82
MutPred		0.49		Loss of catalytic residue at V137 (P = 0.004);Loss of catalytic residue at V137 (P = 0.004);Loss of catalytic residue at V137 (P = 0.004);Loss of catalytic residue at V137 (P = 0.004);Loss of catalytic residue at V137 (P = 0.004);Loss of catalytic residue at V137 (P = 0.004);.;
MVP		0.90
MPC		0.90
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
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: rs1554300601; hg19: chr7-34009948;