rs281875326
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001614.5(ACTG1):c.464C>T(p.Ser155Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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
12
2
1
Clinical Significance
Conservation
PhyloP100: 9.50
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001614.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ACTG1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.93
PP5
?
Variant 17-81511526-G-A is Pathogenic according to our data. Variant chr17-81511526-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511526-G-A is described in Lovd as [Pathogenic]. Variant chr17-81511526-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTG1 | NM_001614.5 | c.464C>T | p.Ser155Phe | missense_variant | 4/6 | ENST00000573283.7 | |
ACTG1 | NM_001199954.3 | c.464C>T | p.Ser155Phe | missense_variant | 4/6 | ||
ACTG1 | NR_037688.3 | n.536C>T | non_coding_transcript_exon_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTG1 | ENST00000573283.7 | c.464C>T | p.Ser155Phe | missense_variant | 4/6 | 5 | NM_001614.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Baraitser-winter syndrome 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 25, 2013 | - - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 28496999, 32506774, 35054877, 27096712, 24268205, 29620237, 32349449, 28439872, 29372643, 28493397, 22366783, 27240540, 30143558) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2023 | The c.464C>T (p.S155F) alteration is located in exon 4 (coding exon 3) of the ACTG1 gene. This alteration results from a C to T substitution at nucleotide position 464, causing the serine (S) at amino acid position 155 to be replaced by a phenylalanine (F)._x000D_ _x000D_ for Baraitser-Winter syndrome; however, its clinical significance for ACTG1-related deafness is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with Baraitser-Winter syndrome, including two de novo occurrences (Rivière, 2012). This amino acid position is highly conserved in available vertebrate species. A functional analysis of the p.S155F alteration demonstrated increased F-actin content and multiple anomalous F-actin rich filopodia-like protrusions compared to control cells (Rivière, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Congenital anomaly of kidney and urinary tract Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 24, 2018 | - - |
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;D;D;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
T
Sift4G
Uncertain
D;D;D;D;D;.;.;.;D;D;D
Polyphen
D;D;D;D;D;D;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);.;Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);Loss of disorder (P = 0.0018);.;
MVP
ClinPred
D
GERP RS
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