rs104894003
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001101.5(ACTB):c.547C>T(p.Arg183Trp) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
ACTB
NM_001101.5 missense
NM_001101.5 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 6.46
Genes affected
ACTB (HGNC:132): (actin beta) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
In a helix (size 12) in uniprot entity ACTB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001101.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-5528536-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 989344.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTB. . Trascript score misZ 7.6852 (greater than threshold 3.09). GenCC has associacion of gene with ACTB-associated syndromic thrombocytopenia, Baraitser-Winter cerebrofrontofacial syndrome, developmental malformations-deafness-dystonia syndrome, Baraitser-Winter syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 7-5528536-G-A is Pathogenic according to our data. Variant chr7-5528536-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5528536-G-A is described in Lovd as [Pathogenic]. Variant chr7-5528536-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTB | NM_001101.5 | c.547C>T | p.Arg183Trp | missense_variant | 4/6 | ENST00000646664.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTB | ENST00000646664.1 | c.547C>T | p.Arg183Trp | missense_variant | 4/6 | NM_001101.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 70
GnomAD4 exome
Cov.:
70
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental malformations-deafness-dystonia syndrome Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Complex loss of function and gain of function are known mechanisms of disease in this gene associated with dystonia (MIM#607371). Additionally, dominant-negative has also been suggested (PMIDs: 25255767, 16685646). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated N-terminally processed cytplasmic 1 actin chain (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has consistently been reported in individuals with dystonia, bilateral hearing loss and/or intellectual disability and has been classified as pathogenic by clinical diagnostic laboratories (PMIDs: 16685646, 28487785, 29788902, 33446253, 30315159; ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patient EBV-transformed lymphoblastoid cells demonstrated defects in cell morphology, less effective depolymerisation of actin cytoskeleton and resistance to lactrunculin A, an actin-monomer sequestering drug, compared control lymphoblastoid cells (PMID: 16685646). (SP) 1207 - Parental origin of the variant is unresolved. While the proband’s mother tested negative for the variant, it should be noted that the proband’s deceased father has not been tested for the variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided, no classification provided | literature only | GeneReviews | - | Associated with the BWCFF syndrome phenotype with early onset, progressive dystonia, and progressive esophageal achalasia. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.547C>T;p.(Arg183Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 18275; PMID: 26583190;16685646; 28487785; 29788902; 31970217) - PS4. This variant is not present in population databases (rs104894003, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 16685646; 28487785; 29788902) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 13, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change is predicted to replace arginine with tryptophan at codon 183 of the ACTB protein (p.Arg183Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the ATP-binding pocket region (PMID: 16685646). There is a large physicochemical difference between arginine and tryptophan. The variant is absent in a large population cohort (PM2; gnomAD v2.1). The variant is recurrent and has been reported in at least six probands with dystonia and sensorineural deafness, including two assumed de novo occurrences (PS4_Supporting, PM6_Strong; PMID: 16685646, 27862284, 28487785, 28849312, 29788902, 31970217). The variant results in altered protein confirmation causing decreased polymerization rates in in vitro functional assays and assessment of patient cells (PS3_Supporting, PP4; PMID: 16685646, 25255767). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/7 algorithms). In addition, ACTB is a gene with a low rate of benign missense variation and missense variants are a common mechanism of disease (PP2; gnomAD v2.1 gene missense constraint). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM6_Strong, PM2, PS3_Supporting, PS4_Supporting, PP2, PP3, PP4. - |
Baraitser-Winter syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 11, 2019 | PS2, PM2, PP2, PP3, PP4, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the ACTB protein (p.Arg183Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ACTB-related dystonia (PMID: 16685646, 28849312, 33446253). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 18275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTB function (PMID: 16685646). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2022 | Functional studies demonstrate that the R183W variant results in altered protein confirmation causing decreased polymerization rates as compared to wild type (Procaccio et al., 2006; Hundt et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25255767, 16685646, 28849312, 27862284, 28487785, 22366783, 27240540, 33446253, 33098801, 31970217, 29788902, 33144682, 35005077, 34008892, 26583190) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 2017 | - - |
ACTB-related BAFopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D;D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;.
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.
REVEL
Pathogenic
Sift4G
Uncertain
D;.;.;.;.
Polyphen
B;B;B;.;.
Vest4
MutPred
Loss of methylation at R183 (P = 0.0677);Loss of methylation at R183 (P = 0.0677);Loss of methylation at R183 (P = 0.0677);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at