rs3924231

Variant names:

• chr8-22192267-A-G
• rs3924231
• NM_006129.5:c.1180+116A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006129.5(BMP1):​c.1180+116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 855,576 control chromosomes in the GnomAD database, including 20,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7012 hom., cov: 33)
  • Exomes 𝑓: 0.18 (13806 hom.)
• Consequence: BMP1 NM_006129.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 8 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

ENSG00000285881 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-22192267-A-G is Benign according to our data. Variant chr8-22192267-A-G is described in ClinVar as Benign. ClinVar VariationId is 675112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.1180+116A>G		intron_variant	Intron 9 of 19	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.1180+116A>G		intron_variant	Intron 9 of 15	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.1251+116A>G		intron_variant	Intron 9 of 19
BMP1	NR_033404.2	n.1251+116A>G		intron_variant	Intron 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP1	ENST00000306385.10	c.1180+116A>G		intron_variant	Intron 9 of 19	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349.13	c.1180+116A>G		intron_variant	Intron 9 of 15	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41350 AN: 151856 Hom.: 6991 Cov.: 33

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.0986

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.184 AC: 129567 AN: 703602 Hom.: 13806 Cov.: 9 AF XY: 0.182 AC XY: 66029 AN XY: 363790

African (AFR) AF: 0.498 AC: 9032 AN: 18138

American (AMR) AF: 0.192 AC: 5594 AN: 29122

Ashkenazi Jewish (ASJ) AF: 0.0944 AC: 1584 AN: 16786

East Asian (EAS) AF: 0.163 AC: 5358 AN: 32936

South Asian (SAS) AF: 0.162 AC: 9611 AN: 59318

European-Finnish (FIN) AF: 0.281 AC: 9900 AN: 35186

Middle Eastern (MID) AF: 0.178 AC: 441 AN: 2474

European-Non Finnish (NFE) AF: 0.171 AC: 81339 AN: 475358

Other (OTH) AF: 0.196 AC: 6708 AN: 34284

GnomAD4 genome AF: 0.273 AC: 41423 AN: 151974 Hom.: 7012 Cov.: 33 AF XY: 0.276 AC XY: 20534 AN XY: 74290

African (AFR) AF: 0.487 AC: 20160 AN: 41374

American (AMR) AF: 0.233 AC: 3568 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0986 AC: 342 AN: 3470

East Asian (EAS) AF: 0.163 AC: 840 AN: 5156

South Asian (SAS) AF: 0.164 AC: 792 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3141 AN: 10576

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11798 AN: 67970

Other (OTH) AF: 0.243 AC: 513 AN: 2110

Alfa AF: 0.196 Hom.: 4356

Bravo AF: 0.275

Asia WGS AF: 0.193 AC: 672 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.66
DANN	Benign	0.72
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3924231; hg19: chr8-22049780;