rs3924229

Variant names:

• chr8-22192379-A-G
• rs3924229
• NM_006129.5:c.1180+228A>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+228A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 452,978 control chromosomes in the GnomAD database, including 4,553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2070 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2483 hom.)
• Consequence: BMP1 NM_006129.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115
• 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=-0.88).
• BP6: Variant 8-22192379-A-G is Benign according to our data. Variant chr8-22192379-A-G is described in ClinVar as Benign. ClinVar VariationId is 680905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.1180+228A>G		intron_variant	Intron 9 of 19	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.1180+228A>G		intron_variant	Intron 9 of 15	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.1251+228A>G		intron_variant	Intron 9 of 19
BMP1	NR_033404.2	n.1251+228A>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+228A>G		intron_variant	Intron 9 of 19	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349.13	c.1180+228A>G		intron_variant	Intron 9 of 15	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23334 AN: 152074 Hom.: 2061 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0857

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.122 AC: 36643 AN: 300786 Hom.: 2483 Cov.: 3 AF XY: 0.122 AC XY: 19364 AN XY: 158606

African (AFR) AF: 0.251 AC: 2168 AN: 8636

American (AMR) AF: 0.0894 AC: 1084 AN: 12122

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 613 AN: 9088

East Asian (EAS) AF: 0.0665 AC: 1288 AN: 19362

South Asian (SAS) AF: 0.131 AC: 4725 AN: 36182

European-Finnish (FIN) AF: 0.148 AC: 2825 AN: 19114

Middle Eastern (MID) AF: 0.152 AC: 194 AN: 1280

European-Non Finnish (NFE) AF: 0.121 AC: 21510 AN: 177672

Other (OTH) AF: 0.129 AC: 2236 AN: 17330

GnomAD4 genome AF: 0.154 AC: 23370 AN: 152192 Hom.: 2070 Cov.: 33 AF XY: 0.153 AC XY: 11419 AN XY: 74426

African (AFR) AF: 0.244 AC: 10133 AN: 41508

American (AMR) AF: 0.109 AC: 1670 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.0861 AC: 445 AN: 5168

South Asian (SAS) AF: 0.126 AC: 606 AN: 4826

European-Finnish (FIN) AF: 0.147 AC: 1562 AN: 10608

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8238 AN: 68006

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.127 Hom.: 2443

Bravo AF: 0.151

Asia WGS AF: 0.113 AC: 395 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	-0.88
CADD	Benign	5.3
DANN	Benign	0.35
PhyloP100		0.12
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: rs3924229; hg19: chr8-22049892;