7-5528536-G-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001101.5(ACTB):c.547C>G(p.Arg183Gly) 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 Likely 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
13
3
1
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 13 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-A is described in ClinVar as [Pathogenic]. Clinvar id is 18275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, ACTB
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
Variant 7-5528536-G-C is Pathogenic according to our data. 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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTB | NM_001101.5 | c.547C>G | p.Arg183Gly | missense_variant | 4/6 | ENST00000646664.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTB | ENST00000646664.1 | c.547C>G | p.Arg183Gly | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ACTB-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 30, 2019 | The ACTB c.547C>G (p.Arg183Gly) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. A different variant affecting the same amino acid residue, p.Arg183Trp, has been reported in at least seven individuals with dystonia, hearing loss and variable additional features (Skogseid et al. 2018). Based on the identification of the variant in a de novo state, its rarity, and literature evidence, the p.Arg183Gly variant is classified as likely pathogenic for ACTB-related disorders. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.
REVEL
Pathogenic
Sift4G
Uncertain
D;.;.;.;.
Polyphen
D;D;D;.;.
Vest4
MutPred
Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);.;.;
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