8-22206834-C-T

Variant names:

• chr8-22206834-C-T
• rs142089697
• NM_006129.5:c.2234-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006129.5(BMP1):​c.2234-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,614,006 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (56 hom.)
• Consequence: BMP1 NM_006129.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.148
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-22206834-C-T is Benign according to our data. Variant chr8-22206834-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00538 (819/152300) while in subpopulation NFE AF = 0.00848 (577/68012). AF 95% confidence interval is 0.00791. There are 9 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	NM_006129.5	MANE Select	c.2234-20C>T		intron	N/A	NP_006120.1
	BMP1	NR_033403.2		n.2305-20C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP1	ENST00000306385.10	TSL:1 MANE Select	c.2234-20C>T		intron	N/A	ENSP00000305714.5
	BMP1	ENST00000520626.6	TSL:1	n.*2766-20C>T		intron	N/A	ENSP00000430015.2
	BMP1	ENST00000520970.5	TSL:1	n.*726-469C>T		intron	N/A	ENSP00000428332.1

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 819 AN: 152182 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00848

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00483 AC: 1212 AN: 251026 AF XY: 0.00468

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00772 AC: 11290 AN: 1461706 Hom.: 56 Cov.: 31 AF XY: 0.00742 AC XY: 5396 AN XY: 727144

African (AFR) AF: 0.00143 AC: 48 AN: 33478

American (AMR) AF: 0.00378 AC: 169 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 97 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86232

European-Finnish (FIN) AF: 0.00229 AC: 122 AN: 53384

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00940 AC: 10457 AN: 1111914

Other (OTH) AF: 0.00580 AC: 350 AN: 60386

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152300 Hom.: 9 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74486

African (AFR) AF: 0.00192 AC: 80 AN: 41568

American (AMR) AF: 0.00758 AC: 116 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00848 AC: 577 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00683 Hom.: 3

Bravo AF: 0.00574

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Osteogenesis imperfecta type 13 Benign:1

Feb 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 15, 2017

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.8
DANN	Benign	0.71
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

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: rs142089697; hg19: chr8-22064347;