dbSNP rs72680532: BMP4:c.370+28G>A (chr14-53951825-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001202.6(BMP4):c.370+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,597,926 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 14 hom., cov: 33)

Exomes 𝑓: 0.011 ( 86 hom. )

Consequence

BMP4
NM_001202.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.703

Publications

1 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):

BMP4-related ocular growth disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
microphthalmia with brain and digit anomalies
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037618577).

BP6

Variant 14-53951825-C-T is Benign according to our data. Variant chr14-53951825-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00838 (1276/152322) while in subpopulation NFE AF = 0.0118 (805/68032). AF 95% confidence interval is 0.0112. There are 14 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
BMP4	NM_001202.6	MANE Select	c.370+28G>A	intron	N/A	NP_001193.2	P12644
BMP4	NM_001347912.1		c.511+28G>A	intron	N/A	NP_001334841.1
BMP4	NM_001347914.2		c.370+28G>A	intron	N/A	NP_001334843.1	P12644

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BMP4	ENST00000245451.9	TSL:1 MANE Select	c.370+28G>A	intron	N/A	ENSP00000245451.4	P12644
BMP4	ENST00000558984.1	TSL:1	c.370+28G>A	intron	N/A	ENSP00000454134.1	P12644
BMP4	ENST00000559087.5	TSL:1	c.370+28G>A	intron	N/A	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes

AF:

0.00839

AC:

1277

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0243

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00773

AC:

1829

AN:

236534

AF XY:

0.00787

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00302

Gnomad ASJ exome

AF:

0.00483

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00706

GnomAD4 exome

AF:

0.0112

AC:

16130

AN:

1445604

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

7745

AN XY:

719400

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33420

American (AMR)

AF:

0.00315

AC:

141

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00459

AC:

120

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000929

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.0237

AC:

928

AN:

39102

Middle Eastern (MID)

AF:

0.00189

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.0128

AC:

14183

AN:

1111552

Other (OTH)

AF:

0.0100

AC:

604

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

889

1778

2668

3557

4446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.00838

AC:

1276

AN:

152322

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

649

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

41564

American (AMR)

AF:

0.00464

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0243

AC:

258

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

805

AN:

68032

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00958

Hom.:

Bravo

AF:

0.00644

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00829

AC:

1001

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.0111

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.84

FATHMM_MKL

Benign

0.36

MetaRNN

Benign

0.0038

PhyloP100

0.70

MVP

0.75

GERP RS

3.0

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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.

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

Computational scores

Splicing

Publications

Other links and lift over