Genetic Variant BMP4:c.-133+501C>A (chr14-53956049-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001202.6(BMP4):c.-133+501C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,512 control chromosomes in the GnomAD database, including 10,333 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 10300 hom., cov: 32)

Exomes 𝑓: 0.39 ( 33 hom. )

Consequence

BMP4
NM_001202.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.55

Publications

12 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:

LOC124903317 (HGNC:):

LOC124903317 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6 link	c.-133+501C>A		intron_variant	Intron 1 of 3	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9 link	c.-133+501C>A		intron_variant	Intron 1 of 3	1	NM_001202.6	ENSP00000245451.4

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52384

AN:

151972

Hom.:

10295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.387

Gnomad ASJ

AF:

0.351

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.365

GnomAD4 exome

AF:

0.389

AC:

165

AN:

424

Hom.:

AF XY:

0.418

AC XY:

102

AN XY:

244

show subpopulations

African (AFR)

AF:

0.100

AC:

AN:

American (AMR)

AF:

0.300

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.429

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.418

AC:

118

AN:

282

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.345

AC:

52406

AN:

152088

Hom.:

10300

Cov.:

AF XY:

0.345

AC XY:

25641

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.143

AC:

5928

AN:

41526

American (AMR)

AF:

0.388

AC:

5925

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.351

AC:

1219

AN:

3468

East Asian (EAS)

AF:

0.451

AC:

2318

AN:

5144

South Asian (SAS)

AF:

0.350

AC:

1684

AN:

4816

European-Finnish (FIN)

AF:

0.444

AC:

4696

AN:

10576

Middle Eastern (MID)

AF:

0.295

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.432

AC:

29360

AN:

67960

Other (OTH)

AF:

0.360

AC:

760

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1698

3396

5095

6793

8491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<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:

0.413

Hom.:

5751

Bravo

AF:

0.339

Asia WGS

AF:

0.351

AC:

1221

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.28

(source)

DANN

Benign

0.92

PhyloP100

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over