4-81045996-G-T

Position:

• chr4-81045996-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001201.5(BMP3):​c.575G>T​(p.Arg192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMP3 NM_001201.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP3	NM_001201.5	c.575G>T	p.Arg192Leu	missense_variant	2/3	ENST00000282701.4	NP_001192.4
BMP3	XM_006714291.4	c.575G>T	p.Arg192Leu	missense_variant	2/3		XP_006714354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP3	ENST00000282701.4	c.575G>T	p.Arg192Leu	missense_variant	2/3	1	NM_001201.5	ENSP00000282701.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.58	P
Vest4		0.41
MutPred		0.49		Loss of MoRF binding (P = 0.0214);
MVP		0.72
MPC		0.30
ClinPred		0.51	D
GERP RS		3.1
Varity_R		0.049
gMVP		0.45

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: rs3733549; hg19: chr4-81967150;