14-53949883-CTTTTTTTTTTT-CTTTTTT

Variant names:

• chr14-53949883-CTTTTT-C
• rs1555339771
• NM_001202.6:c.*144_*148delAAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001202.6(BMP4):​c.*144_*148delAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 644,316 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.425
• 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.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00035 (47/134410) while in subpopulation AMR AF = 0.000912 (12/13152). AF 95% confidence interval is 0.000526. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.*144_*148delAAAAA		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*144_*148delAAAAA		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*144_*148delAAAAA		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.*144_*148delAAAAA		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*144_*148delAAAAA		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*144_*148delAAAAA		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.000350 AC: 47 AN: 134410 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000912

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000479

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000641 AC: 327 AN: 509906 Hom.: 4 AF XY: 0.000632 AC XY: 163 AN XY: 257844

African (AFR) AF: 0.000242 AC: 3 AN: 12420

American (AMR) AF: 0.000400 AC: 6 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12402

East Asian (EAS) AF: 0.00 AC: 0 AN: 28834

South Asian (SAS) AF: 0.000102 AC: 3 AN: 29396

European-Finnish (FIN) AF: 0.0000403 AC: 1 AN: 24810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1930

European-Non Finnish (NFE) AF: 0.000828 AC: 297 AN: 358890

Other (OTH) AF: 0.000648 AC: 17 AN: 26222

GnomAD4 genome AF: 0.000350 AC: 47 AN: 134410 Hom.: 0 Cov.: 0 AF XY: 0.000325 AC XY: 21 AN XY: 64670

African (AFR) AF: 0.000119 AC: 4 AN: 33616

American (AMR) AF: 0.000912 AC: 12 AN: 13152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3272

East Asian (EAS) AF: 0.00 AC: 0 AN: 4534

South Asian (SAS) AF: 0.00 AC: 0 AN: 3556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000479 AC: 31 AN: 64760

Other (OTH) AF: 0.00 AC: 0 AN: 1894

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42

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;