14-53949883-C-CATT

Position:

• chr14-53949883-C-CATT

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
• 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

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/exons	MANE	Protein	UniProt
BMP4	NM_001202.6	c.*148_*149insAAT		3_prime_UTR_variant	4/4	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9	c.*148_*149insAAT		3_prime_UTR_variant	4/4	1	NM_001202.6	ENSP00000245451	P1
BMP4	ENST00000558984.1	c.*148_*149insAAT		3_prime_UTR_variant	3/3	1		ENSP00000454134	P1
BMP4	ENST00000559087.5	c.*148_*149insAAT		3_prime_UTR_variant	4/4	1		ENSP00000453485	P1
BMP4	ENST00000417573.5	c.*148_*149insAAT		3_prime_UTR_variant	4/4	5		ENSP00000394165	P1

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

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.: 0 AF XY: 0.0442 AC XY: 2861 AN XY: 64688

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:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cleft Lip +/- Cleft Palate, Autosomal Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Syndromic Microphthalmia, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Orofacial cleft Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

BMP4-Related Syndromic Microphthalmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;