dbSNP rs387906992: BMPER:p.Gln309Lys (chr7-34055301-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001365308.1(BMPER):c.925C>A(p.Gln309Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMPER
NM_001365308.1 missense, splice_region

Scores

Splicing: ADA: 0.009321

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.10

Publications

0 publications found

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 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

BMPER links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20655945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPER	NM_001365308.1 link	c.925C>A	p.Gln309Lys	missense_variant, splice_region_variant	Exon 9 of 15	ENST00000649409.2	NP_001352237.1
BMPER	NM_133468.5 link	c.925C>A	p.Gln309Lys	missense_variant, splice_region_variant	Exon 10 of 16		NP_597725.1	Q8N8U9A0A090N7U6
BMPER	NM_001410872.1 link	c.925C>A	p.Gln309Lys	missense_variant, splice_region_variant	Exon 9 of 14		NP_001397801.1
BMPER	XM_047419939.1 link	c.271C>A	p.Gln91Lys	missense_variant, splice_region_variant	Exon 4 of 10		XP_047275895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPER	ENST00000649409.2 link	c.925C>A	p.Gln309Lys	missense_variant, splice_region_variant	Exon 9 of 15		NM_001365308.1	ENSP00000497748.1		Q8N8U9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727162

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.053

T;.;T;.;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.21

.;T;T;T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.17

T;T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.5

L;.;L;.;.;.;.

PhyloP100

4.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.91

N;.;.;.;.;.;.

REVEL

Benign

0.097

Sift

Benign

0.44

T;.;.;.;.;.;.

Sift4G

Benign

0.73

T;.;.;.;.;.;.

Polyphen

0.015

B;.;B;.;.;.;.

Vest4

0.25

MutPred

0.62

Gain of methylation at Q309 (P = 0.0065);Gain of methylation at Q309 (P = 0.0065);Gain of methylation at Q309 (P = 0.0065);Gain of methylation at Q309 (P = 0.0065);Gain of methylation at Q309 (P = 0.0065);Gain of methylation at Q309 (P = 0.0065);.;

MVP

0.83

MPC

0.25

ClinPred

0.37

GERP RS

5.2

Varity_R

0.20

gMVP

0.43

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0093

dbscSNV1_RF

Benign

0.16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over