8-22165406-A-C

Variant names:

• chr8-22165406-A-C
• NM_006129.5:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_006129.5(BMP1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMP1 NM_006129.5 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 155 codons. Genomic position: 22176562. Lost 0.156 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22165406-A-C is Pathogenic according to our data. Variant chr8-22165406-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3692495.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 20	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.35A>C		non_coding_transcript_exon_variant	Exon 1 of 20
BMP1	NR_033404.2	n.35A>C		non_coding_transcript_exon_variant	Exon 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP1	ENST00000306385.10	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 20	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349.13	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Benign	-0.55	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.0010	B;.;.;B
Vest4		0.89
MutPred		1.0		Gain of methylation at R6 (P = 0.1058);Gain of methylation at R6 (P = 0.1058);Gain of methylation at R6 (P = 0.1058);Gain of methylation at R6 (P = 0.1058);
MVP		0.92
ClinPred		0.80	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-22022919;