Genetic Variant NM_001202.6:c.*148A>T (chr14-53949884-T-A) – 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.*148A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.12 ( 10 hom. )

Consequence

BMP4
NM_001202.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.04

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):

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 (BayesDel_noAF=-0.94).

BP6

Variant 14-53949884-T-A is Benign according to our data. Variant chr14-53949884-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (53/32640) while in subpopulation AFR AF = 0.00239 (26/10876). AF 95% confidence interval is 0.00167. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 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.*148A>T	3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
BMP4	NM_001347912.1		c.*148A>T	3_prime_UTR	Exon 4 of 4	NP_001334841.1
BMP4	NM_001347914.2		c.*148A>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.*148A>T	3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
BMP4	ENST00000558984.1	TSL:1	c.*148A>T	3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
BMP4	ENST00000559087.5	TSL:1	c.*148A>T	3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

AN:

32632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

Gnomad ASJ

AF:

0.00146

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00846

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00238

GnomAD4 exome

AF:

0.121

AC:

10566

AN:

87308

Hom.:

Cov.:

AF XY:

0.124

AC XY:

5370

AN XY:

43366

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0732

AC:

151

AN:

2062

American (AMR)

AF:

0.121

AC:

173

AN:

1434

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

197

AN:

1856

East Asian (EAS)

AF:

0.0681

AC:

102

AN:

1498

South Asian (SAS)

AF:

0.152

AC:

382

AN:

2506

European-Finnish (FIN)

AF:

0.159

AC:

764

AN:

4796

Middle Eastern (MID)

AF:

0.108

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.120

AC:

8269

AN:

68646

Other (OTH)

AF:

0.118

AC:

497

AN:

4224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.277

Heterozygous variant carriers

1014

2028

3042

4056

5070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<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:

0.00162

AC:

AN:

32640

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

AN XY:

16170

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

10876

American (AMR)

AF:

0.00103

AC:

AN:

4862

Ashkenazi Jewish (ASJ)

AF:

0.00146

AC:

AN:

684

East Asian (EAS)

AF:

0.00

AC:

AN:

2624

South Asian (SAS)

AF:

0.00

AC:

AN:

1728

European-Finnish (FIN)

AF:

0.00846

AC:

AN:

946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

10168

Other (OTH)

AF:

0.00235

AC:

AN:

426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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:

0.000389

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Microphthalmia with brain and digit anomalies (1)

not provided (1)

Orofacial cleft 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.099

(source)

DANN

Benign

0.25

PhyloP100

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over