8-22195610-T-C

Variant names:

• chr8-22195610-T-C
• rs4075478
• NM_006129.5:c.1765+23T>C

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.1765+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,602,902 control chromosomes in the GnomAD database, including 127,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16955 hom., cov: 30)
  • Exomes 𝑓: 0.39 (110485 hom.)
• Consequence: BMP1 NM_006129.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0340
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-22195610-T-C is Benign according to our data. Variant chr8-22195610-T-C is described in ClinVar as Benign. ClinVar VariationId is 674968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

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.1765+23T>C		intron	N/A	NP_006120.1
	BMP1	NM_001199.4	MANE Plus Clinical	c.1765+23T>C		intron	N/A	NP_001190.1
	BMP1	NR_033403.2		n.1836+23T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	ENST00000306385.10	TSL:1 MANE Select	c.1765+23T>C		intron	N/A	ENSP00000305714.5
	BMP1	ENST00000306349.13	TSL:1 MANE Plus Clinical	c.1765+23T>C		intron	N/A	ENSP00000306121.8
	BMP1	ENST00000471755.5	TSL:1	n.1765+23T>C		intron	N/A	ENSP00000428665.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69595 AN: 151656 Hom.: 16918 Cov.: 30

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.425 AC: 100276 AN: 236138 AF XY: 0.414

Gnomad AFR exome AF: 0.621

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.545

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.385 AC: 558826 AN: 1451132 Hom.: 110485 Cov.: 40 AF XY: 0.384 AC XY: 277064 AN XY: 722008

African (AFR) AF: 0.619 AC: 20142 AN: 32558

American (AMR) AF: 0.541 AC: 22953 AN: 42430

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10216 AN: 25838

East Asian (EAS) AF: 0.567 AC: 22126 AN: 39022

South Asian (SAS) AF: 0.393 AC: 33375 AN: 84876

European-Finnish (FIN) AF: 0.408 AC: 21349 AN: 52356

Middle Eastern (MID) AF: 0.347 AC: 1804 AN: 5194

European-Non Finnish (NFE) AF: 0.363 AC: 402715 AN: 1108980

Other (OTH) AF: 0.403 AC: 24146 AN: 59878

GnomAD4 genome AF: 0.459 AC: 69678 AN: 151770 Hom.: 16955 Cov.: 30 AF XY: 0.462 AC XY: 34235 AN XY: 74168

African (AFR) AF: 0.616 AC: 25519 AN: 41394

American (AMR) AF: 0.489 AC: 7473 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1394 AN: 3470

East Asian (EAS) AF: 0.557 AC: 2863 AN: 5140

South Asian (SAS) AF: 0.391 AC: 1881 AN: 4808

European-Finnish (FIN) AF: 0.425 AC: 4454 AN: 10472

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.363 AC: 24680 AN: 67916

Other (OTH) AF: 0.446 AC: 938 AN: 2102

Alfa AF: 0.397 Hom.: 21271

Bravo AF: 0.472

Asia WGS AF: 0.510 AC: 1775 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Osteogenesis imperfecta type 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.33
PhyloP100		-0.034
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs4075478; hg19: chr8-22053123; COSMIC: COSV60479757; COSMIC: COSV60479757;