Genetic Variant NM_001202.6:c.-132-934C>A (chr14-53954334-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.-132-934C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 151,798 control chromosomes in the GnomAD database, including 10,373 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 0.35 ( 10373 hom., cov: 30)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

BMP4
NM_001202.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.128

Publications

23 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=-0.74).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6 link	c.-132-934C>A		intron_variant	Intron 1 of 3	ENST00000245451.9	NP_001193.2	P12644Q53XC5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMP4	ENST00000245451.9 link	c.-132-934C>A	intron_variant	Intron 1 of 3	1	NM_001202.6	ENSP00000245451.4	P12644
BMP4	ENST00000559087.5 link	c.-132-934C>A	intron_variant	Intron 1 of 3	1		ENSP00000453485.1	P12644
BMP4	ENST00000417573.5 link	c.-133+87C>A	intron_variant	Intron 1 of 3	5		ENSP00000394165.1	P12644
BMP4	ENST00000559642.1 link	c.-132-934C>A	intron_variant	Intron 1 of 2	3		ENSP00000453467.1	H0YM53

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52542

AN:

151642

Hom.:

10368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.390

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.452

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.303

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.366

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

AF XY:

0.281

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.300

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.200

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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

AF:

0.346

AC:

52569

AN:

151762

Hom.:

10373

Cov.:

AF XY:

0.347

AC XY:

25712

AN XY:

74112

show subpopulations

African (AFR)

AF:

0.144

AC:

5955

AN:

41434

American (AMR)

AF:

0.390

AC:

5950

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

1219

AN:

3466

East Asian (EAS)

AF:

0.452

AC:

2315

AN:

5118

South Asian (SAS)

AF:

0.353

AC:

1689

AN:

4786

European-Finnish (FIN)

AF:

0.447

AC:

4697

AN:

10508

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29464

AN:

67884

Other (OTH)

AF:

0.361

AC:

762

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1620

3240

4859

6479

8099

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:

0.401

Hom.:

23799

Bravo

AF:

0.340

Asia WGS

AF:

0.353

AC:

1227

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.7

(source)

DANN

Benign

0.79

PhyloP100

0.13

PromoterAI

-0.044

Neutral

(source)

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