chr8-22165406-A-G

Position:

chr8-22165406-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_006129.5(BMP1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000803 in 1,494,830 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

BMP1
NM_006129.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.23

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_006129.5 (BMP1) was described as [Pathogenic] in ClinVar as 1433797

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-22165406-A-G is Pathogenic according to our data. Variant chr8-22165406-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2987540.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BMP1	NM_006129.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/20	ENST00000306385.10
BMP1	NM_001199.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/16	ENST00000306349.13
BMP1	NR_033403.2 linkuse as main transcript	n.35A>G		non_coding_transcript_exon_variant	1/20
BMP1	NR_033404.2 linkuse as main transcript	n.35A>G		non_coding_transcript_exon_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP1	ENST00000306385.10 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/20	1	NM_006129.5	P1	P13497-1
BMP1	ENST00000306349.13 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/16	1	NM_001199.4		P13497-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000819

AC:

AN:

1342674

Hom.:

Cov.:

AF XY:

0.00000603

AC XY:

AN XY:

663438

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000104

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2023

This sequence change affects the initiator methionine of the BMP1 mRNA. The next in-frame methionine is located at codon 155. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BMP1-related conditions. This variant disrupts a region of the BMP1 protein in which other variant(s) (p.Gly12Arg) have been determined to be pathogenic (PMID: 22482805, 24091809, 29499418). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.40

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.0010

B;.;.;B

Vest4

0.86

MutPred

1.0

Loss of disorder (P = 0.1132);Loss of disorder (P = 0.1132);Loss of disorder (P = 0.1132);Loss of disorder (P = 0.1132);

MVP

0.92

ClinPred

0.84

GERP RS

3.3

Varity_R

0.93

gMVP

0.59

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