chr8-22165428-CGCTGCTGCTCGG-C

Variant names:

• chr8-22165428-CGCTGCTGCTCGG-C
• NM_006129.5:c.33_44delCGGGCTGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_006129.5(BMP1):​c.33_44delCGGGCTGCTGCT​(p.Gly12_Leu15del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMP1 NM_006129.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.02

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.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006129.5.
• PP5: Variant 8-22165428-CGCTGCTGCTCGG-C is Pathogenic according to our data. Variant chr8-22165428-CGCTGCTGCTCGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3639674.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.33_44delCGGGCTGCTGCT	p.Gly12_Leu15del	disruptive_inframe_deletion	Exon 1 of 20	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.33_44delCGGGCTGCTGCT	p.Gly12_Leu15del	disruptive_inframe_deletion	Exon 1 of 16	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.67_78delCGGGCTGCTGCT		non_coding_transcript_exon_variant	Exon 1 of 20
BMP1	NR_033404.2	n.67_78delCGGGCTGCTGCT		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.33_44delCGGGCTGCTGCT	p.Gly12_Leu15del	disruptive_inframe_deletion	Exon 1 of 20	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349.13	c.33_44delCGGGCTGCTGCT	p.Gly12_Leu15del	disruptive_inframe_deletion	Exon 1 of 16	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.33_44del, results in the deletion of 4 amino acid(s) of the BMP1 protein (p.Gly12_Leu15del), but otherwise preserves the integrity of the reading frame. 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. -

not specified Uncertain:1

Jan 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BMP1 c.33_44del12 (p.Gly12_Leu15del) results in an in-frame deletion that is predicted to remove five amino acids from the encoded protein. The variant was absent in 168982 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.33_44del12 in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.34G>C, &same_codon_pdot&), supporting the critical relevance of codon 12 to BMP1 protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr8-22022941;