14-53949883-C-CATTT

Variant names:

• chr14-53949883-C-CATTT
• rs796563569
• NM_001202.6:c.*148_*149insAAAT

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149insAAAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (26 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00176 (236/134404) while in subpopulation EAS AF = 0.0319 (144/4518). AF 95% confidence interval is 0.0276. There are 4 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.*148_*149insAAAT		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*148_*149insAAAT		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*148_*149insAAAT		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_*149insAAAT		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*148_*149insAAAT		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*148_*149insAAAT		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 237 AN: 134410 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.00141

Gnomad FIN AF: 0.00129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000926

Gnomad OTH AF: 0.00106

GnomAD4 exome AF: 0.00359 AC: 1826 AN: 508858 Hom.: 26 Cov.: 0 AF XY: 0.00370 AC XY: 953 AN XY: 257300

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

African (AFR) AF: 0.00363 AC: 45 AN: 12410

American (AMR) AF: 0.00207 AC: 31 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.00315 AC: 39 AN: 12372

East Asian (EAS) AF: 0.0120 AC: 344 AN: 28658

South Asian (SAS) AF: 0.00566 AC: 166 AN: 29346

European-Finnish (FIN) AF: 0.00190 AC: 47 AN: 24760

Middle Eastern (MID) AF: 0.00155 AC: 3 AN: 1930

European-Non Finnish (NFE) AF: 0.00288 AC: 1030 AN: 358226

Other (OTH) AF: 0.00462 AC: 121 AN: 26180

⚠️ 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: 0.00176 AC: 236 AN: 134404 Hom.: 4 Cov.: 0 AF XY: 0.00178 AC XY: 115 AN XY: 64696

African (AFR) AF: 0.00196 AC: 66 AN: 33674

American (AMR) AF: 0.000152 AC: 2 AN: 13162

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

East Asian (EAS) AF: 0.0319 AC: 144 AN: 4518

South Asian (SAS) AF: 0.00142 AC: 5 AN: 3532

European-Finnish (FIN) AF: 0.00129 AC: 11 AN: 8500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.0000927 AC: 6 AN: 64750

Other (OTH) AF: 0.00105 AC: 2 AN: 1898

Alfa AF: 0.00 Hom.: 747

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.0

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;