14-53949883-C-CATT

Variant names:

• chr14-53949883-C-CATT
• rs796563569
• NM_001202.6:c.*148_*149insAAT

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149insAAT 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 0.045 (149 hom., cov: 0)
  • Exomes 𝑓: 0.048 (249 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: 2 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 (EAS) allele frequency at 95% confidence interval = 0.061 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.*148_*149insAAT		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*148_*149insAAT		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*148_*149insAAT		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.*148_*149insAAT		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*148_*149insAAT		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*148_*149insAAT		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6022 AN: 134394 Hom.: 147 Cov.: 0

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.0281

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0651

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0404

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0566

GnomAD4 exome AF: 0.0476 AC: 24032 AN: 505274 Hom.: 249 Cov.: 0 AF XY: 0.0476 AC XY: 12154 AN XY: 255582

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

African (AFR) AF: 0.0463 AC: 567 AN: 12254

American (AMR) AF: 0.0321 AC: 477 AN: 14848

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 821 AN: 12220

East Asian (EAS) AF: 0.0420 AC: 1192 AN: 28384

South Asian (SAS) AF: 0.0533 AC: 1556 AN: 29170

European-Finnish (FIN) AF: 0.0484 AC: 1191 AN: 24608

Middle Eastern (MID) AF: 0.0585 AC: 111 AN: 1896

European-Non Finnish (NFE) AF: 0.0475 AC: 16894 AN: 355946

Other (OTH) AF: 0.0471 AC: 1223 AN: 25948

⚠️ 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: 0.0448 AC: 6027 AN: 134388 Hom.: 149 Cov.: 0 AF XY: 0.0442 AC XY: 2861 AN XY: 64688

African (AFR) AF: 0.0633 AC: 2130 AN: 33664

American (AMR) AF: 0.0318 AC: 418 AN: 13164

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 249 AN: 3272

East Asian (EAS) AF: 0.0647 AC: 292 AN: 4516

South Asian (SAS) AF: 0.0507 AC: 179 AN: 3532

European-Finnish (FIN) AF: 0.0365 AC: 310 AN: 8502

Middle Eastern (MID) AF: 0.0410 AC: 10 AN: 244

European-Non Finnish (NFE) AF: 0.0356 AC: 2302 AN: 64744

Other (OTH) AF: 0.0596 AC: 113 AN: 1896

Alfa AF: 0.0192 Hom.: 747

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: rs796563569; hg19: chr14-54416601;