Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001202.6(BMP4):c.1037C>T(p.Ala346Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMP4
NM_001202.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.99

Publications

7 publications found

Variant links:

Genes affected

BMP4 (HGNC:1071): (bone morphogenetic protein 4) 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 regulates heart development and adipogenesis. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. The encoded protein may also be involved in the pathology of multiple cardiovascular diseases and human cancers. [provided by RefSeq, Jul 2016]

BMP4 Gene-Disease associations (from GenCC):

microphthalmia with brain and digit anomalies
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Stickler syndrome
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
orofacial cleft 11
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

BMP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001202.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMP4	NM_001202.6	MANE Select	c.1037C>T	p.Ala346Val	missense	Exon 4 of 4	NP_001193.2
BMP4	NM_001347912.1		c.1178C>T	p.Ala393Val	missense	Exon 4 of 4	NP_001334841.1
BMP4	NM_001347914.2		c.1037C>T	p.Ala346Val	missense	Exon 3 of 3	NP_001334843.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMP4	ENST00000245451.9	TSL:1 MANE Select	c.1037C>T	p.Ala346Val	missense	Exon 4 of 4	ENSP00000245451.4
BMP4	ENST00000558984.1	TSL:1	c.1037C>T	p.Ala346Val	missense	Exon 3 of 3	ENSP00000454134.1
BMP4	ENST00000559087.5	TSL:1	c.1037C>T	p.Ala346Val	missense	Exon 4 of 4	ENSP00000453485.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 (1)

Orofacial cleft 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.054

Polyphen

0.97

Vest4

0.40

MutPred

0.71

Gain of catalytic residue at C341 (P = 0.0146)

MVP

0.90

MPC

0.85

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.73

Mutation Taster

=2/98

disease causing (ClinVar)

(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.

14-53950222-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over