chr15-34794799-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_005159.5(ACTC1):c.10G>A(p.Asp4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ACTC1
NM_005159.5 missense
NM_005159.5 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
ACTC1 (HGNC:143): (actin alpha cardiac muscle 1) Actins are highly conserved proteins that are involved in various types of cell motility. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The protein encoded by this gene belongs to the actin family which is comprised of three main groups of actin isoforms, alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Defects in this gene have been associated with idiopathic dilated cardiomyopathy (IDC) and familial hypertrophic cardiomyopathy (FHC). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTC1. . Gene score misZ 4.5244 (greater than the threshold 3.09). Trascript score misZ 6.3156 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, atrial septal defect 5, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1R, hypertrophic cardiomyopathy 11.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTC1 | NM_005159.5 | c.10G>A | p.Asp4Asn | missense_variant | 2/7 | ENST00000290378.6 | NP_005150.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.10G>A | p.Asp4Asn | missense_variant | 2/7 | 1 | NM_005159.5 | ENSP00000290378.4 | ||
ACTC1 | ENST00000560563.2 | n.116G>A | non_coding_transcript_exon_variant | 2/6 | 2 | |||||
GJD2-DT | ENST00000503496.6 | n.300-15697C>T | intron_variant | 2 | ||||||
GJD2-DT | ENST00000671663.1 | n.95-15697C>T | intron_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250544Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135562
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461104Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726754
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 07, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4 of the ACTC1 protein (p.Asp4Asn). This variant is present in population databases (no rsID available, gnomAD 0.004%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 538810). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 21, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2019 | The p.D4N variant (also known as c.10G>A), located in coding exon 1 of the ACTC1 gene, results from a G to A substitution at nucleotide position 10. The aspartic acid at codon 4 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of disorder (P = 0.1555);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at