rs74486266

Variant names:

• chr14-53952147-A-G
• rs74486266
• NM_001202.6:c.76T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001347913.2(BMP4):​c.-114T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,140 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: BMP4 NM_001347913.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.49
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-53952147-A-G is Benign according to our data. Variant chr14-53952147-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468357.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (302/152316) while in subpopulation NFE AF = 0.00347 (236/68018). AF 95% confidence interval is 0.00311. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347913.2. 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.76T>C	p.Leu26Leu	synonymous	Exon 3 of 4	NP_001193.2	P12644
	BMP4	NM_001347913.2		c.-114T>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	NP_001334842.1
	BMP4	NM_001347915.2		c.-114T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	NP_001334844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP4	ENST00000245451.9	TSL:1 MANE Select	c.76T>C	p.Leu26Leu	synonymous	Exon 3 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.76T>C	p.Leu26Leu	synonymous	Exon 2 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.76T>C	p.Leu26Leu	synonymous	Exon 3 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00162 AC: 406 AN: 251328 AF XY: 0.00167

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00277 AC: 4051 AN: 1461824 Hom.: 7 Cov.: 32 AF XY: 0.00267 AC XY: 1945 AN XY: 727208

African (AFR) AF: 0.000538 AC: 18 AN: 33474

American (AMR) AF: 0.000716 AC: 32 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00348 AC: 3865 AN: 1111970

Other (OTH) AF: 0.00195 AC: 118 AN: 60394

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74480

African (AFR) AF: 0.000601 AC: 25 AN: 41584

American (AMR) AF: 0.00229 AC: 35 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00347 AC: 236 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Microphthalmia with brain and digit anomalies (1)
-	-	1	Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 (1)
-	-	1	not specified (1)
-	1	-	Orofacial cleft 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		3.5
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs74486266; hg19: chr14-54418865; COSMIC: COSV55415334; COSMIC: COSV55415334;