14-53958429-T-C

Variant names:

• chr14-53958429-T-C
• rs2032423
• ENST00000559642.1:c.-133+291A>G

Variant summary

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

The ENST00000559642.1(BMP4):​c.-133+291A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,132 control chromosomes in the GnomAD database, including 25,969 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 0.58 (25969 hom., cov: 33)
• Consequence: BMP4 ENST00000559642.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• Publications: 8 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903317	XM_047432035.1	c.428+2101T>C		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+291A>G		intron_variant	Intron 1 of 2	3		ENSP00000453467.1
ENSG00000287156	ENST00000667337.2	n.1658+2101T>C		intron_variant	Intron 1 of 1
ENSG00000287156	ENST00000754318.1	n.307+1332T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88747 AN: 152014 Hom.: 25955 Cov.: 33

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.586

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

GnomAD4 genome AF: 0.584 AC: 88797 AN: 152132 Hom.: 25969 Cov.: 33 AF XY: 0.587 AC XY: 43665 AN XY: 74358

African (AFR) AF: 0.586 AC: 24312 AN: 41500

American (AMR) AF: 0.584 AC: 8930 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2261 AN: 3470

East Asian (EAS) AF: 0.541 AC: 2794 AN: 5160

South Asian (SAS) AF: 0.664 AC: 3206 AN: 4828

European-Finnish (FIN) AF: 0.589 AC: 6222 AN: 10562

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.575 AC: 39130 AN: 67996

Other (OTH) AF: 0.591 AC: 1249 AN: 2114

Alfa AF: 0.576 Hom.: 12697

Bravo AF: 0.577

Asia WGS AF: 0.631 AC: 2194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.2
DANN	Benign	0.67
PhyloP100		0.082
PromoterAI		0.010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2032423; hg19: chr14-54425147;