chr14-53949901-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001202.6(BMP4):c.*131A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 901,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

BMP4
NM_001202.6 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 1.14

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000253 (190/751126) while in subpopulation EAS AF = 0.000831 (26/31292). AF 95% confidence interval is 0.000582. There are 0 homozygotes in GnomAdExome4. There are 101 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*131A>T	3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
BMP4	NM_001347912.1		c.*131A>T	3_prime_UTR	Exon 4 of 4	NP_001334841.1
BMP4	NM_001347914.2		c.*131A>T	3_prime_UTR	Exon 3 of 3	NP_001334843.1	P12644

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BMP4	ENST00000245451.9	TSL:1 MANE Select	c.*131A>T	3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
BMP4	ENST00000558984.1	TSL:1	c.*131A>T	3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
BMP4	ENST00000559087.5	TSL:1	c.*131A>T	3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

150564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000326

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000253

AC:

190

AN:

751126

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

101

AN XY:

373478

show subpopulations

African (AFR)

AF:

0.0000582

AC:

AN:

17170

American (AMR)

AF:

0.000176

AC:

AN:

17086

Ashkenazi Jewish (ASJ)

AF:

0.000136

AC:

AN:

14706

East Asian (EAS)

AF:

0.000831

AC:

AN:

31292

South Asian (SAS)

AF:

0.000205

AC:

AN:

38952

European-Finnish (FIN)

AF:

0.000141

AC:

AN:

28440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2658

European-Non Finnish (NFE)

AF:

0.000240

AC:

136

AN:

565874

Other (OTH)

AF:

0.000286

AC:

AN:

34948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000146

AC:

AN:

150676

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

73614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41012

American (AMR)

AF:

0.00

AC:

AN:

15098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000326

AC:

AN:

67578

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000491

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cleft Lip +/- Cleft Palate, Autosomal Dominant (1)

Orofacial cleft 11 (1)

Syndromic Microphthalmia, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.9

(source)

DANN

Benign

0.66

PhyloP100

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