rs144030074

Variant names:

• chr7-33937289-A-G
• rs144030074
• NM_001365308.1:c.220A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001365308.1(BMPER):​c.220A>G​(p.Asn74Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00255 in 1,613,806 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: BMPER NM_001365308.1 missense, splice_region
• Scores: Splicing: ADA: 0.4087
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.19
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013875514).
• BP6: Variant 7-33937289-A-G is Benign according to our data. Variant chr7-33937289-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402429.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00146 (222/152294) while in subpopulation SAS AF = 0.0029 (14/4826). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPER	NM_001365308.1	MANE Select	c.220A>G	p.Asn74Asp	missense splice_region	Exon 3 of 15	NP_001352237.1
	BMPER	NM_133468.5		c.220A>G	p.Asn74Asp	missense splice_region	Exon 4 of 16	NP_597725.1
	BMPER	NM_001410872.1		c.220A>G	p.Asn74Asp	missense splice_region	Exon 3 of 14	NP_001397801.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPER	ENST00000649409.2	MANE Select	c.220A>G	p.Asn74Asp	missense splice_region	Exon 3 of 15	ENSP00000497748.1
	BMPER	ENST00000297161.6	TSL:1	c.220A>G	p.Asn74Asp	missense splice_region	Exon 4 of 16	ENSP00000297161.2
	BMPER	ENST00000650544.1		c.220A>G	p.Asn74Asp	missense splice_region	Exon 3 of 14	ENSP00000497982.1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00175 AC: 440 AN: 251354 AF XY: 0.00197

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00267 AC: 3899 AN: 1461512 Hom.: 9 Cov.: 31 AF XY: 0.00262 AC XY: 1904 AN XY: 727102

African (AFR) AF: 0.000418 AC: 14 AN: 33466

American (AMR) AF: 0.000984 AC: 44 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00223 AC: 192 AN: 86248

European-Finnish (FIN) AF: 0.000842 AC: 45 AN: 53414

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00304 AC: 3376 AN: 1111702

Other (OTH) AF: 0.00371 AC: 224 AN: 60380

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74470

African (AFR) AF: 0.000313 AC: 13 AN: 41564

American (AMR) AF: 0.00163 AC: 25 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68026

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

Alfa AF: 0.00218 Hom.: 1

Bravo AF: 0.00150

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00182 AC: 221

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Diaphanospondylodysostosis (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.16
Sift	Benign	0.043	D
Sift4G	Benign	0.068	T
Polyphen		0.058	B
Vest4		0.64
MVP		0.83
MPC		0.53
ClinPred		0.026	T
GERP RS		5.1
Varity_R		0.42
gMVP		0.59
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.41
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.010		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: rs144030074; hg19: chr7-33976901; COSMIC: COSV99032547;