4-81031549-C-G

Variant names:

• chr4-81031549-C-G
• rs1478763551
• NM_001201.5:c.265C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001201.5(BMP3):​c.265C>G​(p.Arg89Gly) 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 benign outcome for this variant. 17/22 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. R89W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMP3 NM_001201.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11084661).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201.5. 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
	BMP3	NM_001201.5	MANE Select	c.265C>G	p.Arg89Gly	missense	Exon 1 of 3	NP_001192.4	P12645

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP3	ENST00000282701.4	TSL:1 MANE Select	c.265C>G	p.Arg89Gly	missense	Exon 1 of 3	ENSP00000282701.2	P12645
	BMP3	ENST00000909109.1		c.265C>G	p.Arg89Gly	missense	Exon 1 of 3	ENSP00000579168.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.056
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.18
Sift	Benign	0.046	D
Sift4G	Uncertain	0.053	T
Polyphen		0.023	B
Vest4		0.19
MutPred		0.36		Loss of MoRF binding (P = 0.0224)
MVP		0.70
MPC		0.15
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.19
Mutation Taster		=92/8	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: rs1478763551; hg19: chr4-81952703; COSMIC: COSV105869672;