rs397517069

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The ENST00000290378.6(ACTC1):​c.7G>C​(p.Asp3His) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D3D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTC1
ENST00000290378.6 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.85
Variant links:
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]
GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTC1NM_005159.5 linkuse as main transcriptc.7G>C p.Asp3His missense_variant 2/7 ENST00000290378.6 NP_005150.1
GJD2-DTNR_120329.1 linkuse as main transcriptn.300-15694C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTC1ENST00000290378.6 linkuse as main transcriptc.7G>C p.Asp3His missense_variant 2/71 NM_005159.5 ENSP00000290378 P1
GJD2-DTENST00000671663.1 linkuse as main transcriptn.95-15694C>G intron_variant, non_coding_transcript_variant
ACTC1ENST00000560563.2 linkuse as main transcriptn.113G>C non_coding_transcript_exon_variant 2/62
GJD2-DTENST00000503496.6 linkuse as main transcriptn.300-15694C>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 18, 2014The Asp3His variant in ACTC1 has not been previously reported in any other famil ies with cardimyopathy and was absent from large population studies. Computation al prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of th e Asp3His variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
CardioboostCm
Uncertain
0.10
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
28
DANN
Benign
0.94
DEOGEN2
Uncertain
0.47
T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.35
N
REVEL
Uncertain
0.62
Sift4G
Uncertain
0.0020
D
Polyphen
0.17
B
Vest4
0.81
MutPred
0.38
Loss of sheet (P = 0.0817);
MVP
0.97
MPC
1.9
ClinPred
0.97
D
GERP RS
4.2
Varity_R
0.49
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517069; hg19: chr15-35087003; API