Genetic Variant BMP4:c.*148_*149insAAT (chr14-53949883-C-CATT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001202.6(BMP4):c.*148_*149insAAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.045 ( 149 hom., cov: 0)

Exomes 𝑓: 0.048 ( 249 hom. )

Consequence

BMP4
NM_001202.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -4.04

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6 link	c.148_149insAAT		3_prime_UTR_variant	Exon 4 of 4	ENST00000245451.9	NP_001193.2	P12644Q53XC5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMP4	ENST00000245451 link	c.148_149insAAT	3_prime_UTR_variant	Exon 4 of 4	1	NM_001202.6	ENSP00000245451.4	P12644
BMP4	ENST00000558984 link	c.148_149insAAT	3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000454134.1	P12644
BMP4	ENST00000559087 link	c.148_149insAAT	3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000453485.1	P12644
BMP4	ENST00000417573 link	c.148_149insAAT	3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000394165.1	P12644

Frequencies

GnomAD3 genomes

AF:

0.0448

AC:

6022

AN:

134394

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0632

Gnomad AMI

AF:

0.0281

Gnomad AMR

AF:

0.0318

Gnomad ASJ

AF:

0.0761

Gnomad EAS

AF:

0.0651

Gnomad SAS

AF:

0.0509

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0404

Gnomad NFE

AF:

0.0356

Gnomad OTH

AF:

0.0566

GnomAD4 exome

AF:

0.0476

AC:

24032

AN:

505274

Hom.:

249

Cov.:

AF XY:

0.0476

AC XY:

12154

AN XY:

255582

show subpopulations

Gnomad4 AFR exome

AF:

0.0463

Gnomad4 AMR exome

AF:

0.0321

Gnomad4 ASJ exome

AF:

0.0672

Gnomad4 EAS exome

AF:

0.0420

Gnomad4 SAS exome

AF:

0.0533

Gnomad4 FIN exome

AF:

0.0484

Gnomad4 NFE exome

AF:

0.0475

Gnomad4 OTH exome

AF:

0.0471

GnomAD4 genome

AF:

0.0448

AC:

6027

AN:

134388

Hom.:

149

Cov.:

AF XY:

0.0442

AC XY:

2861

AN XY:

64688

show subpopulations

Gnomad4 AFR

AF:

0.0633

Gnomad4 AMR

AF:

0.0318

Gnomad4 ASJ

AF:

0.0761

Gnomad4 EAS

AF:

0.0647

Gnomad4 SAS

AF:

0.0507

Gnomad4 FIN

AF:

0.0365

Gnomad4 NFE

AF:

0.0356

Gnomad4 OTH

AF:

0.0596

Alfa

AF:

0.0192

Hom.:

747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cleft Lip +/- Cleft Palate, Autosomal Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Syndromic Microphthalmia, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Orofacial cleft

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BMP4-Related Syndromic Microphthalmia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over