chr14-53949883-C-CTTT

Variant names:

• chr14-53949883-C-CTTT
• rs1555339771
• NM_001202.6:c.*146_*148dupAAA

Variant summary

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

The NM_001202.6(BMP4):​c.*146_*148dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (457 hom., cov: 0)
  • Exomes 𝑓: 0.0067 (2 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -4.04
• Publications: 0 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 (AFR) allele frequency at 95% confidence interval = 0.163 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.*146_*148dupAAA		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*146_*148dupAAA		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*146_*148dupAAA		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.*146_*148dupAAA		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*146_*148dupAAA		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*146_*148dupAAA		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 7250 AN: 134232 Hom.: 455 Cov.: 0

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0293

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0476

GnomAD4 exome AF: 0.00667 AC: 3389 AN: 508272 Hom.: 2 Cov.: 0 AF XY: 0.00611 AC XY: 1572 AN XY: 257090

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

African (AFR) AF: 0.0640 AC: 769 AN: 12008

American (AMR) AF: 0.00857 AC: 128 AN: 14934

Ashkenazi Jewish (ASJ) AF: 0.00973 AC: 120 AN: 12332

East Asian (EAS) AF: 0.000173 AC: 5 AN: 28836

South Asian (SAS) AF: 0.00105 AC: 31 AN: 29386

European-Finnish (FIN) AF: 0.00691 AC: 171 AN: 24736

Middle Eastern (MID) AF: 0.0130 AC: 25 AN: 1922

European-Non Finnish (NFE) AF: 0.00523 AC: 1871 AN: 358076

Other (OTH) AF: 0.0103 AC: 269 AN: 26042

⚠️ 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: 0.0541 AC: 7264 AN: 134226 Hom.: 457 Cov.: 0 AF XY: 0.0529 AC XY: 3418 AN XY: 64608

African (AFR) AF: 0.166 AC: 5584 AN: 33550

American (AMR) AF: 0.0332 AC: 437 AN: 13144

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 96 AN: 3272

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4518

South Asian (SAS) AF: 0.00368 AC: 13 AN: 3532

European-Finnish (FIN) AF: 0.0128 AC: 109 AN: 8484

Middle Eastern (MID) AF: 0.0248 AC: 6 AN: 242

European-Non Finnish (NFE) AF: 0.0143 AC: 928 AN: 64736

Other (OTH) AF: 0.0475 AC: 90 AN: 1894

Alfa AF: 0.00266 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1555339771; hg19: chr14-54416601;