rs786205220

Variant names:

• chr8-22194174-G-C
• rs786205220
• NM_006129.5:c.1297G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-22194174-G-C
• chr8-22194174-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_006129.5(BMP1):​c.1297G>C​(p.Ala433Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A433S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BMP1 NM_006129.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.90
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-22194174-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 190234.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 20	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 16	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.1368G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 20
BMP1	NR_033404.2	n.1368G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP1	ENST00000306385.10	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 20	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349.13	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 16	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.96	D;P
Vest4		0.89
MutPred		0.64		Loss of stability (P = 0.159);Loss of stability (P = 0.159);
MVP		0.53
MPC		0.68
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.83
gMVP		0.84
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

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

Other links and lift over

dbSNP: rs786205220; hg19: chr8-22051687;