rs121912765

chr14-53951945-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP3_ModeratePP5BS1_SupportingBS2

The NM_001202.6(BMP4):c.278A>G(p.Glu93Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000491 in 1,608,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

BMP4
NM_001202.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.11

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

PP5

Variant 14-53951945-T-C is Pathogenic according to our data. Variant chr14-53951945-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17701.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000535 (78/1456586) while in subpopulation NFE AF= 0.0000656 (73/1111976). AF 95% confidence interval is 0.0000533. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP4	NM_001202.6 linkuse as main transcript	c.278A>G	p.Glu93Gly	missense_variant	3/4	ENST00000245451.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP4	ENST00000245451.9 linkuse as main transcript	c.278A>G	p.Glu93Gly	missense_variant	3/4	1	NM_001202.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

246266

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1456586

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

724912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000656

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000413

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Microphthalmia with brain and digit anomalies

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.15

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.41

T;T;T;T;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.051

MutationAssessor

Uncertain

2.0

M;M;M;M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.19

T;T;T;T;T;T;D

Sift4G

Benign

0.24

T;T;T;T;.;D;.

Polyphen

1.0

D;D;D;D;.;.;.

Vest4

0.80

MutPred

0.76

Gain of catalytic residue at R88 (P = 0.0118);Gain of catalytic residue at R88 (P = 0.0118);Gain of catalytic residue at R88 (P = 0.0118);Gain of catalytic residue at R88 (P = 0.0118);.;.;Gain of catalytic residue at R88 (P = 0.0118);

MVP

0.85

MPC

0.62

ClinPred

0.72

GERP RS

5.1

Varity_R

0.27

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over