14-53955681-C-G

Variant names:

• chr14-53955681-C-G
• rs2738265
• NM_001202.6:c.-133+869G>C

Variant summary

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

The NM_001347912.1(BMP4):​c.62+1078G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,970 control chromosomes in the GnomAD database, including 25,358 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 (25353 hom., cov: 31)
  • Exomes 𝑓: 0.55 (5 hom.)
• Consequence: BMP4 NM_001347912.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 13 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347912.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	NM_001202.6	MANE Select	c.-133+869G>C		intron	N/A	NP_001193.2
	BMP4	NM_001347912.1		c.62+1078G>C		intron	N/A	NP_001334841.1
	BMP4	NM_130850.5		c.-133+1078G>C		intron	N/A	NP_570911.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	ENST00000245451.9	TSL:1 MANE Select	c.-133+869G>C		intron	N/A	ENSP00000245451.4
	BMP4	ENST00000559087.5	TSL:1	c.-133+1078G>C		intron	N/A	ENSP00000453485.1
	BMP4	ENST00000890807.1		c.-1188G>C		5_prime_UTR	Exon 1 of 4	ENSP00000560866.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87569 AN: 151808 Hom.: 25334 Cov.: 31

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.545 AC: 24 AN: 44 Hom.: 5 Cov.: 0 AF XY: 0.531 AC XY: 17 AN XY: 32

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 16 AN: 32

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.577 AC: 87629 AN: 151926 Hom.: 25353 Cov.: 31 AF XY: 0.580 AC XY: 43044 AN XY: 74256

African (AFR) AF: 0.600 AC: 24840 AN: 41432

American (AMR) AF: 0.583 AC: 8902 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2251 AN: 3466

East Asian (EAS) AF: 0.546 AC: 2786 AN: 5098

South Asian (SAS) AF: 0.644 AC: 3102 AN: 4820

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

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 37965 AN: 67946

Other (OTH) AF: 0.587 AC: 1239 AN: 2110

Alfa AF: 0.463 Hom.: 1291

Bravo AF: 0.573

Asia WGS AF: 0.632 AC: 2198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.33
PhyloP100		-1.1
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)		0.060		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: rs2738265; hg19: chr14-54422399;