rs527604798

Variant names:

• chr8-22165280-G-A
• rs527604798
• ENST00000518913.5:n.-126G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-22165280-G-A
• chr8-22165280-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.01
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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: 89 AN: 152178 Hom.: 0 Cov.: 33

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.: 0 Cov.: 13 AF XY: 0.000764 AC XY: 367 AN XY: 480316

African (AFR) AF: 0.000158 AC: 3 AN: 18962

American (AMR) AF: 0.000724 AC: 6 AN: 8288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14690

East Asian (EAS) AF: 0.00 AC: 0 AN: 25418

South Asian (SAS) AF: 0.0000233 AC: 1 AN: 42968

European-Finnish (FIN) AF: 0.000197 AC: 6 AN: 30390

Middle Eastern (MID) AF: 0.00137 AC: 4 AN: 2926

European-Non Finnish (NFE) AF: 0.000889 AC: 707 AN: 795044

Other (OTH) AF: 0.000812 AC: 34 AN: 41884

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74462

African (AFR) AF: 0.000144 AC: 6 AN: 41580

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000741 Hom.: 0

Bravo AF: 0.000710

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Interstitial lung disease 2 (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)
-	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	17
DANN	Benign	0.96
PhyloP100		1.0
PromoterAI		-0.058	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Mutation Taster		=300/0	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: rs527604798; hg19: chr8-22022793;