NM_001202.6:c.*148_*149delAG

Variant names:

• chr14-53949882-CCT-C
• rs140085940
• NM_001202.6:c.*148_*149delAG

Variant summary

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

The NM_001202.6(BMP4):​c.*148_*149delAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 588,672 control chromosomes in the GnomAD database, including 139 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (117 hom., cov: 0)
  • Exomes 𝑓: 0.017 (22 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: -1.04
• Publications: 1 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 (AFR) allele frequency at 95% confidence interval = 0.0973 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_*149delAG		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*148_*149delAG		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*148_*149delAG		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_*149delAG		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*148_*149delAG		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*148_*149delAG		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 4377 AN: 93662 Hom.: 119 Cov.: 0

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00157

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00198

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.00214

Gnomad MID AF: 0.0787

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0452

GnomAD4 exome AF: 0.0166 AC: 8225 AN: 495006 Hom.: 22 AF XY: 0.0180 AC XY: 4541 AN XY: 252182

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

African (AFR) AF: 0.0633 AC: 887 AN: 14004

American (AMR) AF: 0.0180 AC: 302 AN: 16752

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 277 AN: 13016

East Asian (EAS) AF: 0.00199 AC: 59 AN: 29638

South Asian (SAS) AF: 0.0584 AC: 1974 AN: 33796

European-Finnish (FIN) AF: 0.00267 AC: 69 AN: 25820

Middle Eastern (MID) AF: 0.0455 AC: 91 AN: 1998

European-Non Finnish (NFE) AF: 0.0121 AC: 4018 AN: 333428

Other (OTH) AF: 0.0206 AC: 548 AN: 26554

⚠️ 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: 0.0468 AC: 4386 AN: 93666 Hom.: 117 Cov.: 0 AF XY: 0.0464 AC XY: 2082 AN XY: 44870

African (AFR) AF: 0.100 AC: 2951 AN: 29424

American (AMR) AF: 0.0271 AC: 281 AN: 10384

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 72 AN: 2228

East Asian (EAS) AF: 0.00198 AC: 8 AN: 4044

South Asian (SAS) AF: 0.0764 AC: 202 AN: 2644

European-Finnish (FIN) AF: 0.00214 AC: 8 AN: 3740

Middle Eastern (MID) AF: 0.0876 AC: 17 AN: 194

European-Non Finnish (NFE) AF: 0.0200 AC: 782 AN: 39038

Other (OTH) AF: 0.0480 AC: 64 AN: 1334

Alfa AF: 0.0250 Hom.: 1

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		-1.0
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: rs140085940; hg19: chr14-54416600;