rs76335800

chr14-53949884-T-Achr14-53949884-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001202.6(BMP4):c.*148A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.12 (10 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-53949884-T-A is Benign according to our data. Variant chr14-53949884-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 313346.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP4	NM_001202.6	c.*148A>T		3_prime_UTR_variant	4/4	ENST00000245451.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP4	ENST00000245451.9	c.*148A>T		3_prime_UTR_variant	4/4	1	NM_001202.6	P1
BMP4	ENST00000558984.1	c.*148A>T		3_prime_UTR_variant	3/3	1		P1
BMP4	ENST00000559087.5	c.*148A>T		3_prime_UTR_variant	4/4	1		P1
BMP4	ENST00000417573.5	c.*148A>T		3_prime_UTR_variant	4/4	5		P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 53 AN: 32632 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00846

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00238

GnomAD4 exome AF: 0.121 AC: 10566 AN: 87308 Hom.: 10 Cov.: 0 AF XY: 0.124 AC XY: 5370 AN XY: 43366

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0681

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.00162 AC: 53 AN: 32640 Hom.: 0 Cov.: 0 AF XY: 0.00167 AC XY: 27 AN XY: 16170

Gnomad4 AFR AF: 0.00239

Gnomad4 AMR AF: 0.00103

Gnomad4 ASJ AF: 0.00146

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00846

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00235

Alfa AF: 0.000389 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Orofacial cleft 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Microphthalmia with brain and digit anomalies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.099
Dann	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs76335800; hg19: chr14-54416602; COSMIC: COSV55414997; COSMIC: COSV55414997;