dbSNP rs786205220: BMP1:p.Ala433Pro (chr8-22194174-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006129.5(BMP1):c.1297G>C(p.Ala433Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BMP1
NM_006129.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.90

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP1	NM_006129.5 link	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 20	ENST00000306385.10	NP_006120.1	P13497-1
BMP1	NM_001199.4 link	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 16	ENST00000306349.13	NP_001190.1	P13497-2
BMP1	NR_033403.2 link	n.1368G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 20
BMP1	NR_033404.2 link	n.1368G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP1	ENST00000306385.10 link	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 20	1	NM_006129.5	ENSP00000305714.5		P13497-1
BMP1	ENST00000306349.13 link	c.1297G>C	p.Ala433Pro	missense_variant, splice_region_variant	Exon 10 of 16	1	NM_001199.4	ENSP00000306121.8		P13497-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.96

D;P

Vest4

0.89

MutPred

0.64

Loss of stability (P = 0.159);Loss of stability (P = 0.159);

MVP

0.53

MPC

0.68

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.83

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over