8-22165391-C-G

Variant names:

• chr8-22165391-C-G
• rs373839736
• NM_006129.5:c.-15C>G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006129.5(BMP1):​c.-15C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,446,040 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: BMP1 NM_006129.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.397

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 8-22165391-C-G is Benign according to our data. Variant chr8-22165391-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 362575.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 = 0.00798 (1215/152268) while in subpopulation NFE AF= 0.0135 (919/67996). AF 95% confidence interval is 0.0128. There are 9 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5	c.-15C>G		5_prime_UTR_variant	Exon 1 of 20	ENST00000306385.10	NP_006120.1
BMP1	NM_001199.4	c.-15C>G		5_prime_UTR_variant	Exon 1 of 16	ENST00000306349.13	NP_001190.1
BMP1	NR_033403.2	n.20C>G		non_coding_transcript_exon_variant	Exon 1 of 20
BMP1	NR_033404.2	n.20C>G		non_coding_transcript_exon_variant	Exon 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP1	ENST00000306385	c.-15C>G		5_prime_UTR_variant	Exon 1 of 20	1	NM_006129.5	ENSP00000305714.5
BMP1	ENST00000306349	c.-15C>G		5_prime_UTR_variant	Exon 1 of 16	1	NM_001199.4	ENSP00000306121.8

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1217 AN: 152164 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00730 AC: 392 AN: 53690 Hom.: 3 AF XY: 0.00739 AC XY: 225 AN XY: 30442

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00534

Gnomad ASJ exome AF: 0.00168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00351

Gnomad FIN exome AF: 0.00468

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00613

GnomAD4 exome AF: 0.0124 AC: 16024 AN: 1293772 Hom.: 130 Cov.: 32 AF XY: 0.0123 AC XY: 7808 AN XY: 635606

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00645

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.0000687

Gnomad4 SAS exome AF: 0.00425

Gnomad4 FIN exome AF: 0.00445

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00798 AC: 1215 AN: 152268 Hom.: 9 Cov.: 33 AF XY: 0.00720 AC XY: 536 AN XY: 74452

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00932 Hom.: 2

Bravo AF: 0.00785

Asia WGS AF: 0.000870 AC: 3 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 01, 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. -

Osteogenesis imperfecta type 13 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Interstitial lung disease 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis Imperfecta, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs373839736; hg19: chr8-22022904;