rs144030074

Positions:

• chr7-33937289-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/23 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

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 Benign. Variant got -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 id is 402429.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPER	NM_001365308.1	c.220A>G	p.Asn74Asp	missense_variant, splice_region_variant	3/15	ENST00000649409.2	NP_001352237.1
BMPER	NM_133468.5	c.220A>G	p.Asn74Asp	missense_variant, splice_region_variant	4/16		NP_597725.1
BMPER	NM_001410872.1	c.220A>G	p.Asn74Asp	missense_variant, splice_region_variant	3/14		NP_001397801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPER	ENST00000649409.2	c.220A>G	p.Asn74Asp	missense_variant, splice_region_variant	3/15		NM_001365308.1	ENSP00000497748	P1

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

GnomAD3 exomes AF: 0.00175 AC: 440 AN: 251354 Hom.: 2 AF XY: 0.00197 AC XY: 268 AN XY: 135840

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 SAS exome AF: 0.00160

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

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00223

Gnomad4 FIN exome AF: 0.000842

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00371

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

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00229 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency. Not reported. Next to splice junction and LOF variants in gene are associated with autosomal recessive diaphanospondylodysostosis. -

Diaphanospondylodysostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.;.;.
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	.;T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D
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;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs144030074; hg19: chr7-33976901; COSMIC: COSV99032547;