14-53949883-C-CAT

Variant names:

• chr14-53949883-C-CAT
• rs796563569
• NM_001202.6:c.*148_*149insAT

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149insAT 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 0.41 (12430 hom., cov: 0)
  • Exomes 𝑓: 0.30 (5314 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 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 (NFE) allele frequency at 95% confidence interval = 0.537 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_*149insAT		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*148_*149insAT		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*148_*149insAT		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_*149insAT		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*148_*149insAT		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*148_*149insAT		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.410 AC: 55100 AN: 134366 Hom.: 12435 Cov.: 0

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.390

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.301 AC: 148551 AN: 493386 Hom.: 5314 Cov.: 0 AF XY: 0.301 AC XY: 74973 AN XY: 249276

African (AFR) AF: 0.119 AC: 1449 AN: 12126

American (AMR) AF: 0.198 AC: 2844 AN: 14342

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 3154 AN: 11856

East Asian (EAS) AF: 0.119 AC: 3329 AN: 27984

South Asian (SAS) AF: 0.225 AC: 6428 AN: 28556

European-Finnish (FIN) AF: 0.340 AC: 8111 AN: 23890

Middle Eastern (MID) AF: 0.245 AC: 458 AN: 1872

European-Non Finnish (NFE) AF: 0.333 AC: 115641 AN: 347478

Other (OTH) AF: 0.282 AC: 7137 AN: 25282

GnomAD4 genome AF: 0.410 AC: 55082 AN: 134360 Hom.: 12430 Cov.: 0 AF XY: 0.409 AC XY: 26416 AN XY: 64664

African (AFR) AF: 0.169 AC: 5697 AN: 33662

American (AMR) AF: 0.348 AC: 4570 AN: 13148

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1371 AN: 3268

East Asian (EAS) AF: 0.193 AC: 870 AN: 4514

South Asian (SAS) AF: 0.379 AC: 1334 AN: 3524

European-Finnish (FIN) AF: 0.584 AC: 4978 AN: 8520

Middle Eastern (MID) AF: 0.381 AC: 93 AN: 244

European-Non Finnish (NFE) AF: 0.541 AC: 35044 AN: 64730

Other (OTH) AF: 0.390 AC: 740 AN: 1896

Alfa AF: 0.305 Hom.: 747

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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		-4.0
Mutation Taster		=92/8	polymorphism

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;