chr8-22197420-G-C

Variant names:

• chr8-22197420-G-C
• rs786205218
• NM_006129.5:c.2107G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006129.5(BMP1):​c.2107G>C​(p.Asp703His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. D703D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMP1 NM_006129.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.98
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-22197420-G-C is Pathogenic according to our data. Variant chr8-22197420-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 190232.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	NM_006129.5	MANE Select	c.2107G>C	p.Asp703His	missense splice_region	Exon 15 of 20	NP_006120.1	P13497-1
	BMP1	NM_001199.4	MANE Plus Clinical	c.2107G>C	p.Glu703Gln	missense splice_region	Exon 15 of 16	NP_001190.1	P13497-2
	BMP1	NR_033403.2		n.2178G>C		splice_region non_coding_transcript_exon	Exon 15 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	ENST00000306385.10	TSL:1 MANE Select	c.2107G>C	p.Asp703His	missense splice_region	Exon 15 of 20	ENSP00000305714.5	P13497-1
	BMP1	ENST00000306349.13	TSL:1 MANE Plus Clinical	c.2107G>C	p.Glu703Gln	missense splice_region	Exon 15 of 16	ENSP00000306121.8	P13497-2
	BMP1	ENST00000471755.5	TSL:1	n.*737G>C		splice_region non_coding_transcript_exon	Exon 15 of 16	ENSP00000428665.1	P13497-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta type 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.39		Gain of methylation at K704 (P = 0.0585)
MVP		0.94
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.63
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205218; hg19: chr8-22054933;