4-81046086-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.93

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 was made for transcript

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
BMP3	NM_001201.5 link	c.665C>T	p.Thr222Met	missense_variant	Exon 2 of 3	ENST00000282701.4	NP_001192.4	P12645
BMP3	XM_006714291.4 link	c.665C>T	p.Thr222Met	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 link	c.665C>T	p.Thr222Met	missense_variant	Exon 2 of 3	1	NM_001201.5	ENSP00000282701.2		P12645

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2986

AN:

152200

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00618

AC:

1550

AN:

250748

AF XY:

0.00525

show subpopulations

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 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.:

Cov.:

AF XY:

0.00276

AC XY:

2007

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0668

AC:

2236

AN:

33472

Gnomad4 AMR exome

AF:

0.00405

AC:

181

AN:

44712

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00795

AC:

686

AN:

86256

Gnomad4 FIN exome

AF:

0.000131

AC:

AN:

53412

Gnomad4 NFE exome

AF:

0.000619

AC:

688

AN:

1111990

Gnomad4 Remaining exome

AF:

0.00553

AC:

334

AN:

60396

Heterozygous variant carriers

263

526

788

1051

1314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0196

AC:

2988

AN:

152318

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1474

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0657

AC:

0.0656641

AN:

0.0656641

Gnomad4 AMR

AF:

0.00903

AC:

0.00902669

AN:

0.00902669

Gnomad4 ASJ

AF:

0.000288

AC:

0.000288018

AN:

0.000288018

Gnomad4 EAS

AF:

0.000193

AC:

0.000192604

AN:

0.000192604

Gnomad4 SAS

AF:

0.00953

AC:

0.00952775

AN:

0.00952775

Gnomad4 FIN

AF:

0.000188

AC:

0.000188288

AN:

0.000188288

Gnomad4 NFE

AF:

0.000588

AC:

0.000587924

AN:

0.000587924

Gnomad4 OTH

AF:

0.0137

AC:

0.0137051

AN:

0.0137051

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00618

Hom.:

111

Bravo

AF:

0.0219

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0620

AC:

273

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00768

AC:

932

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

REVEL

Benign

0.22

Sift

Uncertain

0.024

Sift4G

Benign

0.061

Polyphen

1.0

Vest4

0.32

MVP

0.88

MPC

0.51

ClinPred

0.029

GERP RS

5.1

Varity_R

0.063

gMVP

0.44

Mutation Taster

=91/9

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

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