rs74495140

Variant names:

• chr14-53949883-C-A
• rs74495140
• NM_001202.6:c.*149G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-53949883-C-A
• chr14-53949883-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001202.6(BMP4):​c.*149G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 134,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000074 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BMP4 NM_001202.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.*149G>T		3_prime_UTR	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.*149G>T		3_prime_UTR	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.*149G>T		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.*149G>T		3_prime_UTR	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.*149G>T		3_prime_UTR	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.*149G>T		3_prime_UTR	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.00000744 AC: 1 AN: 134406 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000588 AC: 3 AN: 509920 Hom.: 0 Cov.: 8 AF XY: 0.00000776 AC XY: 2 AN XY: 257854

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

African (AFR) AF: 0.00 AC: 0 AN: 12420

American (AMR) AF: 0.00 AC: 0 AN: 15004

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 28836

South Asian (SAS) AF: 0.00 AC: 0 AN: 29396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24810

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

European-Non Finnish (NFE) AF: 0.00000557 AC: 2 AN: 358898

Other (OTH) AF: 0.0000381 AC: 1 AN: 26224

⚠️ 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: 0.00000744 AC: 1 AN: 134400 Hom.: 0 Cov.: 26 AF XY: 0.0000155 AC XY: 1 AN XY: 64692

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

African (AFR) AF: 0.00 AC: 0 AN: 33674

American (AMR) AF: 0.00 AC: 0 AN: 13162

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4516

South Asian (SAS) AF: 0.00 AC: 0 AN: 3532

European-Finnish (FIN) AF: 0.000118 AC: 1 AN: 8500

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64748

Other (OTH) AF: 0.00 AC: 0 AN: 1898

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.39
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs74495140; hg19: chr14-54416601;