14-53949881-TC-T

Variant names:

• chr14-53949881-TC-T
• rs878985651
• NM_001202.6:c.*150delG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001202.6(BMP4):​c.*150delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 718,476 control chromosomes in the GnomAD database, including 91 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (48 hom., cov: 30)
  • Exomes 𝑓: 0.0089 (43 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: -0.138
• 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):

• BMP4-related ocular growth disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• microphthalmia with brain and digit anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001202.6. 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.*150delG		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*150delG		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*150delG		3_prime_UTR	Exon 3 of 3	NP_001334843.1	P12644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	ENST00000245451.9	TSL:1 MANE Select	c.*150delG		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*150delG		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*150delG		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 1606 AN: 113536 Hom.: 48 Cov.: 30

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0111

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.00570

Gnomad MID AF: 0.0148

Gnomad NFE AF: 0.00599

Gnomad OTH AF: 0.0137

GnomAD4 exome AF: 0.00887 AC: 5364 AN: 604870 Hom.: 43 Cov.: 6 AF XY: 0.0112 AC XY: 3445 AN XY: 306826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00299 AC: 48 AN: 16070

American (AMR) AF: 0.0190 AC: 338 AN: 17784

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 98 AN: 14314

East Asian (EAS) AF: 0.00573 AC: 179 AN: 31220

South Asian (SAS) AF: 0.0735 AC: 3058 AN: 41604

European-Finnish (FIN) AF: 0.00291 AC: 80 AN: 27516

Middle Eastern (MID) AF: 0.0174 AC: 39 AN: 2244

European-Non Finnish (NFE) AF: 0.00287 AC: 1216 AN: 423558

Other (OTH) AF: 0.0101 AC: 308 AN: 30560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0141 AC: 1600 AN: 113606 Hom.: 48 Cov.: 30 AF XY: 0.0180 AC XY: 993 AN XY: 55266

African (AFR) AF: 0.00138 AC: 46 AN: 33268

American (AMR) AF: 0.0386 AC: 483 AN: 12510

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 30 AN: 2696

East Asian (EAS) AF: 0.0174 AC: 83 AN: 4776

South Asian (SAS) AF: 0.155 AC: 611 AN: 3942

European-Finnish (FIN) AF: 0.00570 AC: 34 AN: 5962

Middle Eastern (MID) AF: 0.0122 AC: 3 AN: 246

European-Non Finnish (NFE) AF: 0.00599 AC: 287 AN: 47900

Other (OTH) AF: 0.0149 AC: 23 AN: 1546

Alfa AF: 0.000990 Hom.: 0

Asia WGS AF: 0.0570 AC: 197 AN: 3450

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	BMP4-Related Syndromic Microphthalmia (2)
-	2	-	Cleft Lip +/- Cleft Palate, Autosomal Dominant (2)
-	2	-	Orofacial cleft (2)
-	2	-	Syndromic Microphthalmia, Dominant (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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: rs878985651; hg19: chr14-54416599;