rs387906993

Variant names:

• chr7-34078887-C-T
• rs387906993
• NM_001365308.1:c.1109C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001365308.1(BMPER):​c.1109C>T​(p.Pro370Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPER NM_001365308.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 7-34078887-C-T is Pathogenic according to our data. Variant chr7-34078887-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30745.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1109C>T	p.Pro370Leu	missense	Exon 12 of 15	NP_001352237.1
	BMPER	NM_133468.5		c.1109C>T	p.Pro370Leu	missense	Exon 13 of 16	NP_597725.1
	BMPER	NM_001410872.1		c.1079-6869C>T		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.1109C>T	p.Pro370Leu	missense	Exon 12 of 15	ENSP00000497748.1
	BMPER	ENST00000297161.6	TSL:1	c.1109C>T	p.Pro370Leu	missense	Exon 13 of 16	ENSP00000297161.2
	BMPER	ENST00000650544.1		c.1004C>T	p.Pro335Leu	missense	Exon 11 of 14	ENSP00000497982.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000653 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diaphanospondylodysostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.0023	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.3	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.81		Loss of phosphorylation at T374 (P = 0.1071)
MVP		0.92
MPC		0.78
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.84
Mutation Taster		=26/74	disease causing (ClinVar)

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: rs387906993; hg19: chr7-34118499;