8-22165407-T-C

Position:

• chr8-22165407-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_006129.5(BMP1):​c.2T>C​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.61

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 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 2987540
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22165407-T-C is Pathogenic according to our data. Variant chr8-22165407-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1433797.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP1	NM_006129.5	c.2T>C	p.Met1?	start_lost	1/20	ENST00000306385.10
BMP1	NM_001199.4	c.2T>C	p.Met1?	start_lost	1/16	ENST00000306349.13
BMP1	NR_033403.2	n.36T>C		non_coding_transcript_exon_variant	1/20
BMP1	NR_033404.2	n.36T>C		non_coding_transcript_exon_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP1	ENST00000306385.10	c.2T>C	p.Met1?	start_lost	1/20	1	NM_006129.5	P1
BMP1	ENST00000306349.13	c.2T>C	p.Met1?	start_lost	1/16	1	NM_001199.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2022

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1433797). This variant has not been reported in the literature in individuals affected with BMP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BMP1 mRNA. The next in-frame methionine is located at codon 155. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.72	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	-0.38	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.0	B;.;.;B
Vest4		0.85
MutPred		0.97		Gain of glycosylation at M1 (P = 0.013);Gain of glycosylation at M1 (P = 0.013);Gain of glycosylation at M1 (P = 0.013);Gain of glycosylation at M1 (P = 0.013);
MVP		0.91
ClinPred		0.87	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.64

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: chr8-22022920;