14-53949883-CT-C

Variant names:

• chr14-53949883-CT-C
• rs1555339771
• NM_001202.6:c.*148delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001202.6(BMP4):​c.*148delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 0)
  • Exomes 𝑓: 0.10 (5 hom.)
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter 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 -10 ACMG points.

• BP6: Variant 14-53949883-CT-C is Benign according to our data. Variant chr14-53949883-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1189262.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0108 (1454/134332) while in subpopulation NFE AF = 0.0129 (834/64728). AF 95% confidence interval is 0.0122. There are 10 homozygotes in GnomAd4. There are 732 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.*148delA		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*148delA		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*148delA		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.*148delA		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*148delA		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*148delA		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1454 AN: 134336 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0327

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00338

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00735

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00847

GnomAD4 exome AF: 0.101 AC: 50353 AN: 500220 Hom.: 5 Cov.: 0 AF XY: 0.101 AC XY: 25526 AN XY: 252876

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

African (AFR) AF: 0.140 AC: 1692 AN: 12074

American (AMR) AF: 0.162 AC: 2360 AN: 14552

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 1406 AN: 12108

East Asian (EAS) AF: 0.224 AC: 6164 AN: 27574

South Asian (SAS) AF: 0.124 AC: 3577 AN: 28900

European-Finnish (FIN) AF: 0.0864 AC: 2099 AN: 24300

Middle Eastern (MID) AF: 0.119 AC: 225 AN: 1896

European-Non Finnish (NFE) AF: 0.0852 AC: 30100 AN: 353104

Other (OTH) AF: 0.106 AC: 2730 AN: 25712

⚠️ 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: 0.0108 AC: 1454 AN: 134332 Hom.: 10 Cov.: 0 AF XY: 0.0113 AC XY: 732 AN XY: 64656

African (AFR) AF: 0.00318 AC: 107 AN: 33666

American (AMR) AF: 0.0126 AC: 166 AN: 13146

Ashkenazi Jewish (ASJ) AF: 0.0327 AC: 107 AN: 3268

East Asian (EAS) AF: 0.00310 AC: 14 AN: 4514

South Asian (SAS) AF: 0.00340 AC: 12 AN: 3532

European-Finnish (FIN) AF: 0.0231 AC: 196 AN: 8486

Middle Eastern (MID) AF: 0.00820 AC: 2 AN: 244

European-Non Finnish (NFE) AF: 0.0129 AC: 834 AN: 64728

Other (OTH) AF: 0.00845 AC: 16 AN: 1894

Alfa AF: 0.00789 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555339771; hg19: chr14-54416601;