rs762642

Variant names:

• chr14-53956335-A-C
• rs762642
• NM_001202.6:c.-133+215T>G

Variant summary

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

The NM_001202.6(BMP4):​c.-133+215T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,032 control chromosomes in the GnomAD database, including 10,261 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 0.35 (10261 hom., cov: 32)
• Consequence: BMP4 NM_001202.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 37 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 (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6	c.-133+215T>G		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.-133+215T>G		intron_variant	Intron 1 of 3	1	NM_001202.6	ENSP00000245451.4

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53783 AN: 151914 Hom.: 10263 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.390

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

GnomAD4 genome AF: 0.354 AC: 53816 AN: 152032 Hom.: 10261 Cov.: 32 AF XY: 0.356 AC XY: 26476 AN XY: 74328

African (AFR) AF: 0.205 AC: 8523 AN: 41476

American (AMR) AF: 0.406 AC: 6199 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1666 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2072 AN: 5156

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4812

European-Finnish (FIN) AF: 0.413 AC: 4366 AN: 10574

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28313 AN: 67938

Other (OTH) AF: 0.392 AC: 829 AN: 2114

Alfa AF: 0.392 Hom.: 31841

Bravo AF: 0.346

Asia WGS AF: 0.352 AC: 1227 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	3.3
DANN	Benign	0.76
PhyloP100		-0.25
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs762642; hg19: chr14-54423053;