chr14-53949883-C-CTTT

Position:

• chr14-53949883-C-CTTT

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149insAAA 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 0.054 (457 hom., cov: 0)
  • Exomes 𝑓: 0.0067 (2 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 (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 7250 AN: 134232 Hom.: 455 Cov.: 0

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0293

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0476

GnomAD4 exome AF: 0.00667 AC: 3389 AN: 508272 Hom.: 2 Cov.: 0 AF XY: 0.00611 AC XY: 1572 AN XY: 257090

Gnomad4 AFR exome AF: 0.0640

Gnomad4 AMR exome AF: 0.00857

Gnomad4 ASJ exome AF: 0.00973

Gnomad4 EAS exome AF: 0.000173

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00691

Gnomad4 NFE exome AF: 0.00523

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0541 AC: 7264 AN: 134226 Hom.: 457 Cov.: 0 AF XY: 0.0529 AC XY: 3418 AN XY: 64608

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0293

Gnomad4 EAS AF: 0.000221

Gnomad4 SAS AF: 0.00368

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0475

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

Sep 02, 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: rs1555339771; hg19: chr14-54416601;