rs3733549

Variant names:

• chr4-81045996-G-A
• rs3733549
• NM_001201.5:c.575G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-81045996-G-A
• chr4-81045996-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001201.5(BMP3):​c.575G>A​(p.Arg192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0806 in 1,613,884 control chromosomes in the GnomAD database, including 6,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.079 (587 hom., cov: 33)
  • Exomes 𝑓: 0.081 (6199 hom.)
• Consequence: BMP3 NM_001201.5 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 2.69
• Publications: 21 publications found

Genes affected

BMP3 (HGNC:1070): (bone morphogenetic protein 3) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein suppresses osteoblast differentiation, and negatively regulates bone density, by modulating TGF-beta receptor availability to other ligands. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019924939).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP3	NM_001201.5	c.575G>A	p.Arg192Gln	missense_variant	Exon 2 of 3	ENST00000282701.4	NP_001192.4
BMP3	XM_006714291.4	c.575G>A	p.Arg192Gln	missense_variant	Exon 2 of 3		XP_006714354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP3	ENST00000282701.4	c.575G>A	p.Arg192Gln	missense_variant	Exon 2 of 3	1	NM_001201.5	ENSP00000282701.2

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152086 Hom.: 589 Cov.: 33

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0593

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0864

GnomAD2 exomes AF: 0.101 AC: 25460 AN: 250960 AF XY: 0.107

Gnomad AFR exome AF: 0.0676

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0606

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0697

Gnomad OTH exome AF: 0.0829

GnomAD4 exome AF: 0.0807 AC: 117951 AN: 1461680 Hom.: 6199 Cov.: 30 AF XY: 0.0851 AC XY: 61915 AN XY: 727160

African (AFR) AF: 0.0696 AC: 2331 AN: 33470

American (AMR) AF: 0.123 AC: 5495 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 1539 AN: 26136

East Asian (EAS) AF: 0.153 AC: 6087 AN: 39700

South Asian (SAS) AF: 0.229 AC: 19718 AN: 86238

European-Finnish (FIN) AF: 0.0550 AC: 2938 AN: 53390

Middle Eastern (MID) AF: 0.0978 AC: 564 AN: 5766

European-Non Finnish (NFE) AF: 0.0668 AC: 74277 AN: 1111886

Other (OTH) AF: 0.0828 AC: 5002 AN: 60388

GnomAD4 genome AF: 0.0792 AC: 12062 AN: 152204 Hom.: 587 Cov.: 33 AF XY: 0.0820 AC XY: 6104 AN XY: 74418

African (AFR) AF: 0.0706 AC: 2929 AN: 41512

American (AMR) AF: 0.111 AC: 1697 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0593 AC: 206 AN: 3472

East Asian (EAS) AF: 0.142 AC: 733 AN: 5178

South Asian (SAS) AF: 0.236 AC: 1137 AN: 4822

European-Finnish (FIN) AF: 0.0502 AC: 532 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0676 AC: 4595 AN: 68012

Other (OTH) AF: 0.0865 AC: 183 AN: 2116

Alfa AF: 0.0699 Hom.: 423

Bravo AF: 0.0792

TwinsUK AF: 0.0685 AC: 254

ALSPAC AF: 0.0628 AC: 242

ESP6500AA AF: 0.0690 AC: 304

ESP6500EA AF: 0.0688 AC: 592

ExAC AF: 0.104 AC: 12678

Asia WGS AF: 0.208 AC: 726 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0671

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Thalidomide response Other:1

-

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

this variant was associated with excellent response to thalidomide (achieving transfusion independence) excellent responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.0
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.7
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.10	T
Polyphen		0.039	B
Vest4		0.021
MPC		0.13
ClinPred		0.017	T
GERP RS		3.1
Varity_R		0.028
gMVP		0.30
Mutation Taster		=77/23	polymorphism (auto)

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: rs3733549; hg19: chr4-81967150; COSMIC: COSV51082416;