Genetic Variant BMP1:p.Arg6Pro (chr8-22165422-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006129.5(BMP1):c.17G>C(p.Arg6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

BMP1
NM_006129.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.739

Publications

0 publications found

Variant links:

Genes affected

BMP1 (HGNC:1067): (bone morphogenetic protein 1) This gene encodes a protein that is capable of inducing formation of cartilage in vivo. Although other bone morphogenetic proteins are members of the TGF-beta superfamily, this gene encodes a protein that is not closely related to other known growth factors. This gene is expressed as alternatively spliced variants that share an N-terminal protease domain but differ in their C-terminal region. [provided by RefSeq, Aug 2008]

BMP1 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 13
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BMP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29542154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMP1	NM_006129.5	MANE Select	c.17G>C	p.Arg6Pro	missense	Exon 1 of 20	NP_006120.1	P13497-1
BMP1	NM_001199.4	MANE Plus Clinical	c.17G>C	p.Arg6Pro	missense	Exon 1 of 16	NP_001190.1	P13497-2
BMP1	NR_033403.2		n.51G>C		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMP1	ENST00000306385.10	TSL:1 MANE Select	c.17G>C	p.Arg6Pro	missense	Exon 1 of 20	ENSP00000305714.5	P13497-1
BMP1	ENST00000306349.13	TSL:1 MANE Plus Clinical	c.17G>C	p.Arg6Pro	missense	Exon 1 of 16	ENSP00000306121.8	P13497-2
BMP1	ENST00000471755.5	TSL:1	n.17G>C		non_coding_transcript_exon	Exon 1 of 16	ENSP00000428665.1	P13497-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

155506

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

7.20e-7

AC:

AN:

1388256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28320

American (AMR)

AF:

0.00

AC:

AN:

32014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23832

East Asian (EAS)

AF:

0.00

AC:

AN:

32494

South Asian (SAS)

AF:

0.00

AC:

AN:

77696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5382

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1081830

Other (OTH)

AF:

0.00

AC:

AN:

56984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.26

PhyloP100

0.74

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.35

MutPred

0.35

Loss of methylation at R6 (P = 0.0197)

MVP

0.84

MPC

0.57

ClinPred

0.86

GERP RS

3.0

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.34

gMVP

0.40

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over