Variant 4-81045947-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001201.5(BMP3):c.526C>A(p.Gln176Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,990 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Q176L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0085 ( 24 hom., cov: 33)

Exomes 𝑓: 0.00093 ( 14 hom. )

Consequence

BMP3
NM_001201.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.06

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051380694).

BP6

Variant 4-81045947-C-A is Benign according to our data. Variant chr4-81045947-C-A is described in ClinVar as [Benign]. Clinvar id is 773708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00846 (1288/152248) while in subpopulation AFR AF= 0.0292 (1213/41534). AF 95% confidence interval is 0.0278. There are 24 homozygotes in gnomad4. There are 650 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP3	NM_001201.5 link	c.526C>A	p.Gln176Lys	missense_variant	2/3	ENST00000282701.4	NP_001192.4	P12645
BMP3	XM_006714291.4 link	c.526C>A	p.Gln176Lys	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.526C>A	p.Gln176Lys	missense_variant	2/3	1	NM_001201.5	ENSP00000282701.2		P12645

Frequencies

GnomAD3 genomes

AF:

0.00846

AC:

1287

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00207

AC:

519

AN:

250972

Hom.:

AF XY:

0.00161

AC XY:

219

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000927

AC:

1355

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

583

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00846

AC:

1288

AN:

152248

Hom.:

Cov.:

AF XY:

0.00873

AC XY:

650

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0292

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00944

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0291

AC:

128

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.24

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.16

Sift

Benign

0.39

Sift4G

Benign

0.61

Polyphen

0.13

Vest4

0.043

MVP

0.72

MPC

0.14

ClinPred

0.023

GERP RS

4.8

Varity_R

0.18

gMVP

0.28

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