Genetic Variant NM_005159.5:c.784A>T (chr15-34792114-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_005159.5(ACTC1):c.784A>T(p.Thr262Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T262T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTC1
NM_005159.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19

Publications

1 publications found

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]

ACTC1 links:

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

GJD2-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005159.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3621956).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005159.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACTC1	NM_005159.5	MANE Select	c.784A>T	p.Thr262Ser	missense	Exon 5 of 7	NP_005150.1
ACTC1	NM_001406482.1		c.784A>T	p.Thr262Ser	missense	Exon 4 of 6	NP_001393411.1
ACTC1	NM_001406483.1		c.784A>T	p.Thr262Ser	missense	Exon 5 of 7	NP_001393412.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.784A>T	p.Thr262Ser	missense	Exon 5 of 7	ENSP00000290378.4
ACTC1	ENST00000713613.1		c.895A>T	p.Thr299Ser	missense	Exon 6 of 8	ENSP00000518909.1
ACTC1	ENST00000868408.1		c.790A>T	p.Thr264Ser	missense	Exon 5 of 7	ENSP00000538467.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

CardioboostCm

Benign

0.040

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.11

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.20

PhyloP100

4.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.0

REVEL

Uncertain

0.49

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.40

MutPred

0.28

Loss of helix (P = 0.0444)

MVP

0.95

MPC

1.4

ClinPred

0.61

GERP RS

4.5

Varity_R

0.37

gMVP

0.84

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over