14-53949901-T-A

Position:

• chr14-53949901-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001202.6(BMP4):​c.*131A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 901,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.14

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000146 (22/150676) while in subpopulation NFE AF= 0.000326 (22/67578). AF 95% confidence interval is 0.00022. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP4	NM_001202.6	c.*131A>T		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.*131A>T		3_prime_UTR_variant	4/4	1	NM_001202.6	ENSP00000245451	P1
BMP4	ENST00000558984.1	c.*131A>T		3_prime_UTR_variant	3/3	1		ENSP00000454134	P1
BMP4	ENST00000559087.5	c.*131A>T		3_prime_UTR_variant	4/4	1		ENSP00000453485	P1
BMP4	ENST00000417573.5	c.*131A>T		3_prime_UTR_variant	4/4	5		ENSP00000394165	P1

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 22 AN: 150564 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000326

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 190 AN: 751126 Hom.: 0 Cov.: 10 AF XY: 0.000270 AC XY: 101 AN XY: 373478

Gnomad4 AFR exome AF: 0.0000582

Gnomad4 AMR exome AF: 0.000176

Gnomad4 ASJ exome AF: 0.000136

Gnomad4 EAS exome AF: 0.000831

Gnomad4 SAS exome AF: 0.000205

Gnomad4 FIN exome AF: 0.000141

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.000286

GnomAD4 genome AF: 0.000146 AC: 22 AN: 150676 Hom.: 0 Cov.: 31 AF XY: 0.0000951 AC XY: 7 AN XY: 73614

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000326

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000491 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

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 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.9
DANN	Benign	0.66

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: rs76149166; hg19: chr14-54416619;