14-53949883-C-CATT

Variant names:

• chr14-53949883-C-CATT
• rs796563569
• NM_001202.6:c.*148_*149insAAT

Variant summary

Our verdict is Benign. The variant received -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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -4.04

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.*148_*149insAAT		3_prime_UTR_variant	Exon 4 of 4	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451	c.*148_*149insAAT		3_prime_UTR_variant	Exon 4 of 4	1	NM_001202.6	ENSP00000245451.4
BMP4	ENST00000558984	c.*148_*149insAAT		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000454134.1
BMP4	ENST00000559087	c.*148_*149insAAT		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000453485.1
BMP4	ENST00000417573	c.*148_*149insAAT		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000394165.1

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6022 AN: 134394 Hom.: 147 Cov.: 0

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.: 0 AF XY: 0.0476 AC XY: 12154 AN XY: 255582

Gnomad4 AFR exome AF: 0.0463 AC: 567 AN: 12254

Gnomad4 AMR exome AF: 0.0321 AC: 477 AN: 14848

Gnomad4 ASJ exome AF: 0.0672 AC: 821 AN: 12220

Gnomad4 EAS exome AF: 0.0420 AC: 1192 AN: 28384

Gnomad4 SAS exome AF: 0.0533 AC: 1556 AN: 29170

Gnomad4 FIN exome AF: 0.0484 AC: 1191 AN: 24608

Gnomad4 NFE exome AF: 0.0475 AC: 16894 AN: 355946

Gnomad4 Remaining exome AF: 0.0471 AC: 1223 AN: 25948

GnomAD4 genome AF: 0.0448 AC: 6027 AN: 134388 Hom.: 149 Cov.: 0 AF XY: 0.0442 AC XY: 2861 AN XY: 64688

Gnomad4 AFR AF: 0.0633 AC: 0.0632723 AN: 0.0632723

Gnomad4 AMR AF: 0.0318 AC: 0.0317533 AN: 0.0317533

Gnomad4 ASJ AF: 0.0761 AC: 0.0761002 AN: 0.0761002

Gnomad4 EAS AF: 0.0647 AC: 0.064659 AN: 0.064659

Gnomad4 SAS AF: 0.0507 AC: 0.0506795 AN: 0.0506795

Gnomad4 FIN AF: 0.0365 AC: 0.036462 AN: 0.036462

Gnomad4 NFE AF: 0.0356 AC: 0.0355554 AN: 0.0355554

Gnomad4 OTH AF: 0.0596 AC: 0.0595992 AN: 0.0595992

Alfa AF: 0.0192 Hom.: 747

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

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
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs796563569; hg19: chr14-54416601;