rs17563

Positions:

chr14-53950804-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001202.6(BMP4):c.455T>C(p.Val152Ala) variant causes a missense change. The variant allele was found at a frequency of 0.519 in 1,612,580 control chromosomes in the GnomAD database, including 227,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16493 hom., cov: 33)

Exomes 𝑓: 0.53 ( 210649 hom. )

Consequence

BMP4
NM_001202.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.23

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.141868E-4).

BP6

Variant 14-53950804-A-G is Benign according to our data. Variant chr14-53950804-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 197190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-53950804-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP4	NM_001202.6 linkuse as main transcript	c.455T>C	p.Val152Ala	missense_variant	4/4	ENST00000245451.9	NP_001193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP4	ENST00000245451.9 linkuse as main transcript	c.455T>C	p.Val152Ala	missense_variant	4/4	1	NM_001202.6	ENSP00000245451	P1

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66805

AN:

152032

Hom.:

16484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.475

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.325

Gnomad FIN

AF:

0.628

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.567

Gnomad OTH

AF:

0.437

GnomAD3 exomes

AF:

0.453

AC:

112585

AN:

248720

Hom.:

28013

AF XY:

0.459

AC XY:

61893

AN XY:

134882

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.477

Gnomad EAS exome

AF:

0.268

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.616

Gnomad NFE exome

AF:

0.560

Gnomad OTH exome

AF:

0.471

GnomAD4 exome

AF:

0.527

AC:

769729

AN:

1460430

Hom.:

210649

Cov.:

AF XY:

0.523

AC XY:

380276

AN XY:

726548

show subpopulations

Gnomad4 AFR exome

AF:

0.240

Gnomad4 AMR exome

AF:

0.299

Gnomad4 ASJ exome

AF:

0.476

Gnomad4 EAS exome

AF:

0.244

Gnomad4 SAS exome

AF:

0.347

Gnomad4 FIN exome

AF:

0.613

Gnomad4 NFE exome

AF:

0.569

Gnomad4 OTH exome

AF:

0.492

GnomAD4 genome

AF:

0.439

AC:

66834

AN:

152150

Hom.:

16493

Cov.:

AF XY:

0.437

AC XY:

32480

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.249

Gnomad4 AMR

AF:

0.346

Gnomad4 ASJ

AF:

0.475

Gnomad4 EAS

AF:

0.260

Gnomad4 SAS

AF:

0.325

Gnomad4 FIN

AF:

0.628

Gnomad4 NFE

AF:

0.567

Gnomad4 OTH

AF:

0.436

Alfa

AF:

0.520

Hom.:

43832

Bravo

AF:

0.412

TwinsUK

AF:

0.577

AC:

2141

ALSPAC

AF:

0.578

AC:

2227

ESP6500AA

AF:

0.258

AC:

1138

ESP6500EA

AF:

0.548

AC:

4715

ExAC

AF:

0.454

AC:

55051

Asia WGS

AF:

0.289

AC:

1004

AN:

3478

EpiCase

AF:

0.542

EpiControl

AF:

0.541

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Microphthalmia with brain and digit anomalies

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cleft Lip +/- Cleft Palate, Autosomal Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Orofacial cleft 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.37

T;T;T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.69

.;.;T;.;T

MetaRNN

Benign

0.00011

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.2

L;L;L;L;.

MutationTaster

Benign

0.0013

P;P;P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.71

N;N;N;N;N

REVEL

Benign

0.067

Sift

Benign

0.40

T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;T;.

Polyphen

0.0020

B;B;B;B;.

Vest4

0.037

MPC

0.59

ClinPred

0.017

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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