chr7-33905659-C-A

Position:

chr7-33905659-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001365308.1(BMPER):c.46C>A(p.Arg16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,324 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

BMPER
NM_001365308.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.89

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05974984).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000151 (22/1461328) while in subpopulation EAS AF= 0.000479 (19/39694). AF 95% confidence interval is 0.000313. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BMPER	NM_001365308.1 linkuse as main transcript	c.46C>A	p.Arg16Ser	missense_variant	1/15	ENST00000649409.2
BMPER	NM_133468.5 linkuse as main transcript	c.46C>A	p.Arg16Ser	missense_variant	2/16
BMPER	NM_001410872.1 linkuse as main transcript	c.46C>A	p.Arg16Ser	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPER	ENST00000649409.2 linkuse as main transcript	c.46C>A	p.Arg16Ser	missense_variant	1/15		NM_001365308.1	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000720

AC:

AN:

250164

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000926

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461328

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.46C>A (p.R16S) alteration is located in exon 1 (coding exon 1) of the BMPER gene. This alteration results from a C to A substitution at nucleotide position 46, causing the arginine (R) at amino acid position 16 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 16 of the BMPER protein (p.Arg16Ser). This variant is present in population databases (rs760953708, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with BMPER-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

T;.;T;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.80

.;T;T;T;T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.060

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;.;N;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.34

N;.;.;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.40

T;.;.;.;.;.

Sift4G

Benign

0.71

T;.;.;.;.;.

Polyphen

0.28

B;.;B;.;.;.

Vest4

0.50

MutPred

0.48

Loss of phosphorylation at S18 (P = 0.1704);Loss of phosphorylation at S18 (P = 0.1704);Loss of phosphorylation at S18 (P = 0.1704);Loss of phosphorylation at S18 (P = 0.1704);Loss of phosphorylation at S18 (P = 0.1704);Loss of phosphorylation at S18 (P = 0.1704);

MVP

0.50

MPC

0.23

ClinPred

0.041

GERP RS

1.8

Varity_R

0.13

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over