Variant 4-81046085-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001201.5(BMP3):c.664A>G(p.Thr222Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T222M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

BMP3
NM_001201.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Variant links:

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]

BMP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027513862).

BS2

High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP3	NM_001201.5 link	c.664A>G	p.Thr222Ala	missense_variant	2/3	ENST00000282701.4	NP_001192.4	P12645
BMP3	XM_006714291.4 link	c.664A>G	p.Thr222Ala	missense_variant	2/3		XP_006714354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP3	ENST00000282701.4 link	c.664A>G	p.Thr222Ala	missense_variant	2/3	1	NM_001201.5	ENSP00000282701.2		P12645

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000586

AC:

147

AN:

250756

Hom.:

AF XY:

0.000664

AC XY:

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000893

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000750

AC:

1097

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000759

AC XY:

552

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000985

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000871

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000617

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000954

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000626

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.664A>G (p.T222A) alteration is located in exon 2 (coding exon 2) of the BMP3 gene. This alteration results from a A to G substitution at nucleotide position 664, causing the threonine (T) at amino acid position 222 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.7

DANN

Benign

0.75

DEOGEN2

Benign

0.34

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.54

M_CAP

Benign

0.025

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.96

REVEL

Benign

0.054

Sift

Benign

0.28

Sift4G

Benign

0.50

Polyphen

0.061

Vest4

0.029

MVP

0.69

MPC

0.12

ClinPred

0.027

GERP RS

2.5

Varity_R

0.047

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over