NM_006129.5:c.808A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_006129.5(BMP1):​c.808A>G​(p.Met270Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M270T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BMP1
NM_006129.5 missense

Scores

12
6
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32

Publications

5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • high bone mass osteogenesis imperfecta
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • osteogenesis imperfecta type 3
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 8-22177929-A-G is Pathogenic according to our data. Variant chr8-22177929-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 190233.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BMP1NM_006129.5 linkc.808A>G p.Met270Val missense_variant Exon 6 of 20 ENST00000306385.10 NP_006120.1 P13497-1
BMP1NM_001199.4 linkc.808A>G p.Met270Val missense_variant Exon 6 of 16 ENST00000306349.13 NP_001190.1 P13497-2
BMP1NR_033403.2 linkn.879A>G non_coding_transcript_exon_variant Exon 6 of 20
BMP1NR_033404.2 linkn.879A>G non_coding_transcript_exon_variant Exon 6 of 16

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BMP1ENST00000306385.10 linkc.808A>G p.Met270Val missense_variant Exon 6 of 20 1 NM_006129.5 ENSP00000305714.5 P13497-1
BMP1ENST00000306349.13 linkc.808A>G p.Met270Val missense_variant Exon 6 of 16 1 NM_001199.4 ENSP00000306121.8 P13497-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461046
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726756
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26112
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39666
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53380
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111402
Other (OTH)
AF:
0.00
AC:
0
AN:
60344
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 13 Pathogenic:1
Feb 01, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.66
D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Pathogenic
4.7
H;H
PhyloP100
9.3
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.83
Gain of phosphorylation at Y272 (P = 0.0964);Gain of phosphorylation at Y272 (P = 0.0964);
MVP
0.82
MPC
1.2
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.99
Mutation Taster
=7/93
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205219; hg19: chr8-22035442; API