Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001200.4(BMP2):c.316G>A(p.Ala106Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,605,084 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

BMP2
NM_001200.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.91

Publications

9 publications found

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]

BMP2 Gene-Disease associations (from GenCC):

short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
brachydactyly type A2
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

BMP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 7 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001200.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	NM_001200.4	MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 2 of 3	NP_001191.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMP2	ENST00000378827.5	TSL:1 MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 2 of 3	ENSP00000368104.3
BMP2	ENST00000936876.1		c.316G>A	p.Ala106Thr	missense	Exon 1 of 2	ENSP00000606935.1
BMP2	ENST00000953442.1		c.316G>A	p.Ala106Thr	missense	Exon 2 of 3	ENSP00000623501.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000248

AC:

AN:

241556

AF XY:

0.0000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000276

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000964

AC:

140

AN:

1452866

Hom.:

Cov.:

AF XY:

0.0000873

AC XY:

AN XY:

721278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.0000451

AC:

AN:

44394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25776

East Asian (EAS)

AF:

0.00339

AC:

134

AN:

39512

South Asian (SAS)

AF:

0.00

AC:

AN:

85694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106182

Other (OTH)

AF:

0.0000334

AC:

AN:

59912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00136

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000410

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

0.0023

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.1

PhyloP100

9.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.87

MutPred

0.26

Gain of glycosylation at A106 (P = 0.0783)

MVP

0.80

MPC

0.59

ClinPred

0.86

GERP RS

5.6

Varity_R

0.49

gMVP

0.70

Mutation Taster

=56/44

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs2273074

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over