20-6770259-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001200.4(BMP2):​c.133C>A​(p.Pro45Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000459 in 1,459,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

BMP2
NM_001200.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92
Variant links:
Genes affected
BMP2 (HGNC:1069): (bone morphogenetic protein 2) 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, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.118276596).
BS2
High AC in GnomAdExome4 at 67 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BMP2NM_001200.4 linkc.133C>A p.Pro45Thr missense_variant 2/3 ENST00000378827.5 NP_001191.1 P12643C8C060

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BMP2ENST00000378827.5 linkc.133C>A p.Pro45Thr missense_variant 2/31 NM_001200.4 ENSP00000368104.3 P12643

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000249
AC:
6
AN:
241350
Hom.:
0
AF XY:
0.0000228
AC XY:
3
AN XY:
131470
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000559
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000459
AC:
67
AN:
1459202
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
725750
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000558
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 06, 2024This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 45 of the BMP2 protein (p.Pro45Thr). This variant is present in population databases (rs757825179, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BMP2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Uncertain
0.97
DEOGEN2
Benign
0.31
T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.3
L
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.34
N
REVEL
Benign
0.073
Sift
Benign
0.14
T
Sift4G
Benign
0.45
T
Polyphen
0.0
B
Vest4
0.11
MutPred
0.41
Gain of phosphorylation at P45 (P = 0.0143);
MVP
0.46
MPC
1.4
ClinPred
0.19
T
GERP RS
3.2
Varity_R
0.073
gMVP
0.58

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: rs757825179; hg19: chr20-6750906; API