rs121912767

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The ENST00000245451.9(BMP4):ā€‹c.272C>Gā€‹(p.Ser91Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,609,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00016 ( 0 hom., cov: 33)
Exomes š‘“: 0.00026 ( 0 hom. )

Consequence

BMP4
ENST00000245451.9 missense

Scores

6
9
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 14-53951951-G-C is Benign according to our data. Variant chr14-53951951-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17703.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000164 (25/152190) while in subpopulation NFE AF= 0.000367 (25/68042). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BMP4NM_001202.6 linkuse as main transcriptc.272C>G p.Ser91Cys missense_variant 3/4 ENST00000245451.9 NP_001193.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BMP4ENST00000245451.9 linkuse as main transcriptc.272C>G p.Ser91Cys missense_variant 3/41 NM_001202.6 ENSP00000245451 P1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152190
Hom.:
0
Cov.:
33
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:
0.000367
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000182
AC:
45
AN:
247294
Hom.:
0
AF XY:
0.000172
AC XY:
23
AN XY:
134078
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:
0.000397
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000261
AC:
380
AN:
1457618
Hom.:
0
Cov.:
32
AF XY:
0.000258
AC XY:
187
AN XY:
725380
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000813
Gnomad4 NFE exome
AF:
0.000330
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152190
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74338
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:
0.000367
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000286
Hom.:
0
Bravo
AF:
0.000166
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.000436
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Orofacial cleft 11 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaNov 25, 2019This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2009- -
Microphthalmia with brain and digit anomalies Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaDec 19, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023BMP4: BS2 -
Microphthalmia with brain and digit anomalies;C2677434:Orofacial cleft 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 02, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.83
D;D;D;D;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
.;.;D;.;D;D;D
M_CAP
Benign
0.068
D
MetaRNN
Uncertain
0.72
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.095
D
MutationAssessor
Pathogenic
3.1
M;M;M;M;.;.;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.9
N;N;N;N;N;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0020
D;D;D;D;D;D;D
Sift4G
Uncertain
0.036
D;D;D;D;.;D;.
Polyphen
1.0
D;D;D;D;.;.;.
Vest4
0.92
MVP
0.87
MPC
1.4
ClinPred
0.42
T
GERP RS
5.1
Varity_R
0.48
gMVP
0.56

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.

Other links and lift over

dbSNP: rs121912767; hg19: chr14-54418669; API