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GeneBe

rs17563

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. 12/19 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

2
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

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]

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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 UniProt
BMP4NM_001202.6 linkuse as main transcriptc.455T>C p.Val152Ala missense_variant 4/4 ENST00000245451.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BMP4ENST00000245451.9 linkuse as main transcriptc.455T>C p.Val152Ala missense_variant 4/41 NM_001202.6 P1

Frequencies

GnomAD3 genomes
AF:
0.439
AC:
66805
AN:
152032
Hom.:
16484
Cov.:
33
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.:
63
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.:
33
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:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 25, 2014- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Microphthalmia with brain and digit anomalies Benign:3
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Cleft Lip +/- Cleft Palate, Autosomal Dominant Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Orofacial cleft 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 02, 2018This 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. -
Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.38
Cadd
Benign
19
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
D
MetaRNN
Benign
0.00011
T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.2
L;L;L;L;.
MutationTaster
Benign
0.0013
P;P;P;P
PrimateAI
Uncertain
0.56
T
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
T
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.

Other links and lift over

dbSNP: rs17563; hg19: chr14-54417522; COSMIC: COSV55416014; COSMIC: COSV55416014; API