8-22165142-CGGAGGGAG-CGGAG

Variant names:

• chr8-22165142-CGGAG-C
• rs750344454
• ENST00000354870.5:c.-247_-244delGGAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000397814.7(BMP1):​c.-247_-244delGGAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 333,266 control chromosomes in the GnomAD database, including 5,840 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (1978 hom., cov: 25)
  • Exomes 𝑓: 0.19 (3862 hom.)
• Consequence: BMP1 ENST00000397814.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.668
• 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: 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 8-22165142-CGGAG-C is Benign according to our data. Variant chr8-22165142-CGGAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362572.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397814.7. 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.-263_-260delGGAG		upstream_gene	N/A	NP_006120.1	P13497-1
	BMP1	NM_001199.4	MANE Plus Clinical	c.-263_-260delGGAG		upstream_gene	N/A	NP_001190.1	P13497-2
	BMP1	NR_033403.2		n.-229_-226delGGAG		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	ENST00000354870.5	TSL:5	c.-247_-244delGGAG		5_prime_UTR	Exon 1 of 21	ENSP00000346941.5	Q3MIM8
	BMP1	ENST00000397814.7	TSL:4	c.-247_-244delGGAG		5_prime_UTR	Exon 1 of 5	ENSP00000380915.4	B7ZKR5
	BMP1	ENST00000306385.10	TSL:1 MANE Select	c.-263_-260delGGAG		upstream_gene	N/A	ENSP00000305714.5	P13497-1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 20974 AN: 121450 Hom.: 1975 Cov.: 25

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.00587

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.173

GnomAD4 exome AF: 0.192 AC: 40629 AN: 211722 Hom.: 3862 AF XY: 0.193 AC XY: 21014 AN XY: 109038

African (AFR) AF: 0.0570 AC: 285 AN: 5000

American (AMR) AF: 0.226 AC: 1076 AN: 4770

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 1310 AN: 7092

East Asian (EAS) AF: 0.00969 AC: 141 AN: 14552

South Asian (SAS) AF: 0.204 AC: 2642 AN: 12930

European-Finnish (FIN) AF: 0.277 AC: 4806 AN: 17368

Middle Eastern (MID) AF: 0.173 AC: 179 AN: 1032

European-Non Finnish (NFE) AF: 0.204 AC: 27665 AN: 135392

Other (OTH) AF: 0.186 AC: 2525 AN: 13586

GnomAD4 genome AF: 0.173 AC: 20987 AN: 121544 Hom.: 1978 Cov.: 25 AF XY: 0.179 AC XY: 10522 AN XY: 58706

African (AFR) AF: 0.0456 AC: 1524 AN: 33410

American (AMR) AF: 0.236 AC: 3007 AN: 12722

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 551 AN: 2978

East Asian (EAS) AF: 0.00588 AC: 19 AN: 3230

South Asian (SAS) AF: 0.226 AC: 766 AN: 3390

European-Finnish (FIN) AF: 0.330 AC: 2362 AN: 7164

Middle Eastern (MID) AF: 0.180 AC: 36 AN: 200

European-Non Finnish (NFE) AF: 0.217 AC: 12180 AN: 56018

Other (OTH) AF: 0.171 AC: 291 AN: 1698

Alfa AF: 0.0452 Hom.: 65

Asia WGS AF: 0.0820 AC: 276 AN: 3368

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs750344454; hg19: chr8-22022655;