chr14-53954901-C-T

Variant names:

• chr14-53954901-C-T
• rs76953585
• NM_001202.6:c.-132-1501G>A

Variant summary

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

The NM_001202.6(BMP4):​c.-132-1501G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 152,294 control chromosomes in the GnomAD database, including 491 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 0.054 (491 hom., cov: 32)
• Consequence: BMP4 NM_001202.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• Publications: 3 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)

LOC124903317 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6	c.-132-1501G>A		intron_variant	Intron 1 of 3	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9	c.-132-1501G>A		intron_variant	Intron 1 of 3	1	NM_001202.6	ENSP00000245451.4
BMP4	ENST00000559087.5	c.-132-1501G>A		intron_variant	Intron 1 of 3	1		ENSP00000453485.1
ENSG00000287156	ENST00000667337.2	n.231C>T		non_coding_transcript_exon_variant	Exon 1 of 2
BMP4	ENST00000559642.1	c.-132-1501G>A		intron_variant	Intron 1 of 2	3		ENSP00000453467.1

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8280 AN: 152176 Hom.: 492 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0147

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0609

Gnomad NFE AF: 0.00989

Gnomad OTH AF: 0.0416

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

GnomAD4 genome AF: 0.0545 AC: 8293 AN: 152294 Hom.: 491 Cov.: 32 AF XY: 0.0546 AC XY: 4067 AN XY: 74470

African (AFR) AF: 0.143 AC: 5931 AN: 41540

American (AMR) AF: 0.0532 AC: 814 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.0143 AC: 74 AN: 5170

South Asian (SAS) AF: 0.126 AC: 611 AN: 4832

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10632

Middle Eastern (MID) AF: 0.0621 AC: 18 AN: 290

European-Non Finnish (NFE) AF: 0.00989 AC: 673 AN: 68028

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0228 Hom.: 22

Bravo AF: 0.0588

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.73
PhyloP100		-0.19
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs76953585; hg19: chr14-54421619;