14-53957320-T-G

Variant names:

• chr14-53957320-T-G
• rs77671695
• ENST00000559642.1:c.-133+1400A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000559642.1(BMP4):​c.-133+1400A>C variant causes a intron change. The variant allele was found at a frequency of 0.0495 in 152,286 control chromosomes in the GnomAD database, including 399 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 0.049 (399 hom., cov: 33)
• Consequence: BMP4 ENST00000559642.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000559642.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	ENST00000559642.1	TSL:3	c.-133+1400A>C		intron	N/A	ENSP00000453467.1
	ENSG00000287156	ENST00000667337.2		n.1658+992T>G		intron	N/A
	ENSG00000287156	ENST00000754318.1		n.307+223T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7527 AN: 152168 Hom.: 400 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0396

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

GnomAD4 genome AF: 0.0495 AC: 7538 AN: 152286 Hom.: 399 Cov.: 33 AF XY: 0.0512 AC XY: 3815 AN XY: 74452

African (AFR) AF: 0.120 AC: 4965 AN: 41520

American (AMR) AF: 0.0515 AC: 789 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5190

South Asian (SAS) AF: 0.171 AC: 827 AN: 4826

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10614

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 690 AN: 68038

Other (OTH) AF: 0.0421 AC: 89 AN: 2116

Alfa AF: 0.0426 Hom.: 69

Bravo AF: 0.0517

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		3.6
PromoterAI		0.032	Neutral

Splicing

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

Other links and lift over

dbSNP: rs77671695; hg19: chr14-54424038;