14-53950508-G-C

Variant names:

• chr14-53950508-G-C
• rs200671094
• NM_001202.6:c.751C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001202.6(BMP4):​c.751C>G​(p.His251Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H251Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMP4 NM_001202.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.98
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

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.751C>G	p.His251Asp	missense	Exon 4 of 4	NP_001193.2	P12644
	BMP4	NM_001347912.1		c.892C>G	p.His298Asp	missense	Exon 4 of 4	NP_001334841.1
	BMP4	NM_001347914.2		c.751C>G	p.His251Asp	missense	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.751C>G	p.His251Asp	missense	Exon 4 of 4	ENSP00000245451.4	P12644
	BMP4	ENST00000558984.1	TSL:1	c.751C>G	p.His251Asp	missense	Exon 3 of 3	ENSP00000454134.1	P12644
	BMP4	ENST00000559087.5	TSL:1	c.751C>G	p.His251Asp	missense	Exon 4 of 4	ENSP00000453485.1	P12644

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.89
MutPred		0.66		Gain of catalytic residue at H247 (P = 0.0255)
MVP		0.91
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.72
Mutation Taster		=13/87	disease causing

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: rs200671094; hg19: chr14-54417226;