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4-81046086-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

4
14

Clinical Significance

Benign criteria provided, single submitter B:1

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]

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ACMG classification

Classification made for transcript

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
BMP3NM_001201.5 linkuse as main transcriptc.665C>T p.Thr222Met missense_variant 2/3 ENST00000282701.4
BMP3XM_006714291.4 linkuse as main transcriptc.665C>T p.Thr222Met missense_variant 2/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMP3ENST00000282701.4 linkuse as main transcriptc.665C>T p.Thr222Met missense_variant 2/31 NM_001201.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0196
AC:
2986
AN:
152200
Hom.:
99
Cov.:
32
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
GnomAD3 exomes
AF:
0.00618
AC:
1550
AN:
250748
Hom.:
34
AF XY:
0.00525
AC XY:
711
AN XY:
135478
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 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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeMay 15, 2018- -

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

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

Other links and lift over

dbSNP: rs34505126; hg19: chr4-81967240; API