rs281875329
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate
The NM_001614.5(ACTG1):c.766C>T(p.Arg256Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★).
Frequency
Genomes: not found (cov: 33)
Consequence
ACTG1
NM_001614.5 missense
NM_001614.5 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 1.05
Genes affected
ACTG1 (HGNC:144): (actin gamma 1) Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ACTG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. Gene score misZ: 3.16 (above the threshold of 3.09). Trascript score misZ: 4.8823 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, Baraitser-Winter cerebrofrontofacial syndrome, autosomal dominant nonsyndromic hearing loss 20.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 17-81511224-G-A is Pathogenic according to our data. Variant chr17-81511224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29590.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511224-G-A is described in Lovd as [Pathogenic]. Variant chr17-81511224-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACTG1 | NM_001614.5 | c.766C>T | p.Arg256Trp | missense_variant | Exon 4 of 6 | ENST00000573283.7 | NP_001605.1 | |
| ACTG1 | NM_001199954.3 | c.766C>T | p.Arg256Trp | missense_variant | Exon 4 of 6 | NP_001186883.1 | ||
| ACTG1 | NR_037688.3 | n.838C>T | non_coding_transcript_exon_variant | Exon 4 of 7 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Baraitser-winter syndrome 2 Pathogenic:2
Dec 02, 2015
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Feb 26, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
- -
Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:1
Feb 26, 2019
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control
- -
Lissencephaly Pathogenic:1
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research
- -
not provided Other:1
-
UniProtKB/Swiss-Prot
Significance: not provided
Review Status: no classification provided
Collection Method: literature only
- -
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;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;.;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;.;.;.;.
REVEL
Pathogenic
Sift4G
Uncertain
D;D;D;D;D;.
Polyphen
D;D;D;D;D;D
Vest4
MutPred
Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);
MVP
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