14-53950070-A-T

Variant names:

• chr14-53950070-A-T
• NM_001202.6:c.1189T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001202.6(BMP4):​c.1189T>A​(p.Tyr397Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMP4 NM_001202.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP4	NM_001202.6	c.1189T>A	p.Tyr397Asn	missense_variant	Exon 4 of 4	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9	c.1189T>A	p.Tyr397Asn	missense_variant	Exon 4 of 4	1	NM_001202.6	ENSP00000245451.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 397 of the BMP4 protein (p.Tyr397Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BMP4-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BMP4 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;D;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.3	H;H;H;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.80		Gain of catalytic residue at Y397 (P = 0.0062);Gain of catalytic residue at Y397 (P = 0.0062);Gain of catalytic residue at Y397 (P = 0.0062);Gain of catalytic residue at Y397 (P = 0.0062);
MVP		0.88
MPC		1.8
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-54416788;