Genetic Variant BMP1:n.-126G>A (chr8-22165280-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The ENST00000397814.7(BMP1):c.-126G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,132,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

BMP1
ENST00000397814.7 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 1.01

Publications

0 publications found

Variant links:

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

BMP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000584 (89/152286) while in subpopulation NFE AF = 0.000971 (66/68006). AF 95% confidence interval is 0.000782. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BMP1	NM_006129.5	MANE Select	c.-126G>A	upstream_gene	N/A	NP_006120.1	P13497-1
BMP1	NM_001199.4	MANE Plus Clinical	c.-126G>A	upstream_gene	N/A	NP_001190.1	P13497-2
BMP1	NR_033403.2		n.-92G>A	upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BMP1	ENST00000518913.5	TSL:1	n.-126G>A	non_coding_transcript_exon	Exon 1 of 16	ENSP00000427950.1	B7ZKR5
BMP1	ENST00000520970.5	TSL:1	n.-126G>A	non_coding_transcript_exon	Exon 1 of 19	ENSP00000428332.1	P13497-2
BMP1	ENST00000518913.5	TSL:1	n.-126G>A	5_prime_UTR	Exon 1 of 16	ENSP00000427950.1	B7ZKR5

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000776

AC:

761

AN:

980570

Hom.:

Cov.:

AF XY:

0.000764

AC XY:

367

AN XY:

480316

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

18962

American (AMR)

AF:

0.000724

AC:

AN:

8288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14690

East Asian (EAS)

AF:

0.00

AC:

AN:

25418

South Asian (SAS)

AF:

0.0000233

AC:

AN:

42968

European-Finnish (FIN)

AF:

0.000197

AC:

AN:

30390

Middle Eastern (MID)

AF:

0.00137

AC:

AN:

2926

European-Non Finnish (NFE)

AF:

0.000889

AC:

707

AN:

795044

Other (OTH)

AF:

0.000812

AC:

AN:

41884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000584

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41580

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000971

AC:

AN:

68006

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000741

Hom.:

Bravo

AF:

0.000710

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease 2 (1)

Osteogenesis Imperfecta, Recessive (1)

Surfactant metabolism dysfunction, pulmonary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.0

PromoterAI

-0.058

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.1

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over