4-81046086-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001201.5(BMP3):c.665C>T(p.Thr222Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,614,156 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T222A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (92 hom.)
• Consequence: BMP3 NM_001201.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.93

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003635615).
• BP6: Variant 4-81046086-C-T is Benign according to our data. Variant chr4-81046086-C-T is described in ClinVar as [Benign]. Clinvar id is 775991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP3	NM_001201.5	c.665C>T	p.Thr222Met	missense_variant	2/3	ENST00000282701.4
BMP3	XM_006714291.4	c.665C>T	p.Thr222Met	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP3	ENST00000282701.4	c.665C>T	p.Thr222Met	missense_variant	2/3	1	NM_001201.5	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2986 AN: 152200 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00618 AC: 1550 AN: 250748 Hom.: 34 AF XY: 0.00525 AC XY: 711 AN XY: 135478

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00787

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00286 AC: 4178 AN: 1461838 Hom.: 92 Cov.: 34 AF XY: 0.00276 AC XY: 2007 AN XY: 727216

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00795

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000619

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.0196 AC: 2988 AN: 152318 Hom.: 97 Cov.: 32 AF XY: 0.0198 AC XY: 1474 AN XY: 74484

Gnomad4 AFR AF: 0.0657

Gnomad4 AMR AF: 0.00903

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00218 Hom.: 11

Bravo AF: 0.0219

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0620 AC: 273

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00768 AC: 932

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 15, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Uncertain	0.024	D
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.88
MPC		0.51
ClinPred		0.029	T
GERP RS		5.1
Varity_R		0.063
gMVP		0.44

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: rs34505126; hg19: chr4-81967240;