14-53949882-CCT-C

Position:

• chr14-53949882-CCT-C

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 588,672 control chromosomes in the GnomAD database, including 139 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (117 hom., cov: 0)
  • Exomes 𝑓: 0.017 (22 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: -1.04

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 = 0.0973 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 4377 AN: 93662 Hom.: 119 Cov.: 0

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00157

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00198

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.00214

Gnomad MID AF: 0.0787

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0452

GnomAD4 exome AF: 0.0166 AC: 8225 AN: 495006 Hom.: 22 AF XY: 0.0180 AC XY: 4541 AN XY: 252182

Gnomad4 AFR exome AF: 0.0633

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.0584

Gnomad4 FIN exome AF: 0.00267

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0468 AC: 4386 AN: 93666 Hom.: 117 Cov.: 0 AF XY: 0.0464 AC XY: 2082 AN XY: 44870

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00198

Gnomad4 SAS AF: 0.0764

Gnomad4 FIN AF: 0.00214

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0480

Alfa AF: 0.0250 Hom.: 1

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 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs140085940; hg19: chr14-54416600;