dbSNP rs2855527: BMP4:c.-133+769G>T (chr14-53957951-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000559642.1(BMP4):c.-133+769G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 152,292 control chromosomes in the GnomAD database, including 70,817 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 0.96 ( 70817 hom., cov: 33)

Consequence

BMP4
ENST00000559642.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.496

Publications

3 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:

ENSG00000287156 (HGNC:):

ENSG00000287156 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=-0.67).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903317	XM_047432035.1 link	c.428+1623C>A		intron_variant	Intron 1 of 1		XP_047287991.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
BMP4	ENST00000559642.1 link	c.-133+769G>T	intron_variant	Intron 1 of 2	3	ENSP00000453467.1
ENSG00000287156	ENST00000667337.2 link	n.1658+1623C>A	intron_variant	Intron 1 of 1
ENSG00000287156	ENST00000754318.1 link	n.307+854C>A	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.963

AC:

146511

AN:

152174

Hom.:

70773

Cov.:

show subpopulations

Gnomad AFR

AF:

0.870

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.988

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.973

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.963

AC:

146612

AN:

152292

Hom.:

70817

Cov.:

AF XY:

0.964

AC XY:

71803

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.870

AC:

36144

AN:

41544

American (AMR)

AF:

0.988

AC:

15123

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5170

AN:

5170

South Asian (SAS)

AF:

1.00

AC:

4816

AN:

4818

European-Finnish (FIN)

AF:

1.00

AC:

10620

AN:

10620

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68006

AN:

68040

Other (OTH)

AF:

0.973

AC:

2055

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

244

488

733

977

1221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.962

Hom.:

13784

Bravo

AF:

0.957

Asia WGS

AF:

0.994

AC:

3457

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.6

(source)

DANN

Benign

0.69

PhyloP100

0.50

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over