14-53958334-C-A

Variant names:

• chr14-53958334-C-A
• rs2761887
• ENST00000559642.1:c.-133+386G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000559642.1(BMP4):​c.-133+386G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,074 control chromosomes in the GnomAD database, including 25,081 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25081 hom., cov: 33)
• Consequence: BMP4 ENST00000559642.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 39 publications found

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]

BMP4 Gene-Disease associations (from GenCC):

• microphthalmia with brain and digit anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Stickler syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 11

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000287156 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903317	XM_047432035.1	c.428+2006C>A		intron_variant	Intron 1 of 1		XP_047287991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000559642.1	c.-133+386G>T		intron_variant	Intron 1 of 2	3		ENSP00000453467.1
ENSG00000287156	ENST00000667337.2	n.1658+2006C>A		intron_variant	Intron 1 of 1
ENSG00000287156	ENST00000754318.1	n.307+1237C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87211 AN: 151956 Hom.: 25065 Cov.: 33

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.676

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.577

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.574 AC: 87263 AN: 152074 Hom.: 25081 Cov.: 33 AF XY: 0.576 AC XY: 42833 AN XY: 74322

African (AFR) AF: 0.584 AC: 24202 AN: 41464

American (AMR) AF: 0.578 AC: 8835 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2123 AN: 3472

East Asian (EAS) AF: 0.538 AC: 2782 AN: 5168

South Asian (SAS) AF: 0.643 AC: 3102 AN: 4824

European-Finnish (FIN) AF: 0.554 AC: 5859 AN: 10576

Middle Eastern (MID) AF: 0.679 AC: 197 AN: 290

European-Non Finnish (NFE) AF: 0.566 AC: 38453 AN: 67976

Other (OTH) AF: 0.582 AC: 1230 AN: 2112

Alfa AF: 0.567 Hom.: 93882

Bravo AF: 0.570

Asia WGS AF: 0.624 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.68
PhyloP100		-0.58
PromoterAI		0.0086	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2761887; hg19: chr14-54425052;