rs1555419008

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_005159.5(ACTC1):​c.69T>G​(p.Phe23Leu) 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTC1
NM_005159.5 missense

Scores

9
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02
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)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.966

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTC1NM_005159.5 linkuse as main transcriptc.69T>G p.Phe23Leu missense_variant 2/7 ENST00000290378.6
GJD2-DTNR_120329.1 linkuse as main transcriptn.300-15756A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTC1ENST00000290378.6 linkuse as main transcriptc.69T>G p.Phe23Leu missense_variant 2/71 NM_005159.5 P1
GJD2-DTENST00000671663.1 linkuse as main transcriptn.95-15756A>C intron_variant, non_coding_transcript_variant
ACTC1ENST00000560563.2 linkuse as main transcriptn.175T>G non_coding_transcript_exon_variant 2/62
GJD2-DTENST00000503496.6 linkuse as main transcriptn.300-15756A>C 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

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2022The p.F23L variant (also known as c.69T>G), located in coding exon 1 of the ACTC1 gene, results from a T to G substitution at nucleotide position 69. The phenylalanine at codon 23 is replaced by leucine, an amino acid with highly similar properties. A different alteration located at the same position, resulting in the same protein change, c.67T>C p.F23L, was observed in two individuals reported to have hypertrophic cardiomyopathy; however, clinical details were limited (Coppini R et al. J Am Coll Cardiol. 2014;64:2589-600). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-2.2
N
REVEL
Pathogenic
0.81
Sift4G
Benign
0.067
T
Polyphen
0.23
B
Vest4
0.84
MutPred
0.86
Loss of catalytic residue at F23 (P = 0.0352);
MVP
1.0
MPC
3.2
ClinPred
0.90
D
GERP RS
-0.64
Varity_R
0.66
gMVP
0.98

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: rs1555419008; hg19: chr15-35086941; API