rs750951965

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_005159.5(ACTC1):c.217A>G(p.Ile73Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I73I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ACTC1
NM_005159.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.02

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]

ACTC1 links:

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

GJD2-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant where missense usually causes diseases, ACTC1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTC1	NM_005159.5 linkuse as main transcript	c.217A>G	p.Ile73Val	missense_variant	3/7	ENST00000290378.6
GJD2-DT	NR_120329.1 linkuse as main transcript	n.299+16051T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTC1	ENST00000290378.6 linkuse as main transcript	c.217A>G	p.Ile73Val	missense_variant	3/7	1	NM_005159.5	P1
GJD2-DT	ENST00000671663.1 linkuse as main transcript	n.95-17014T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251472

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2015

The p.Ile73Val variant in ACTC1 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact the protein. In summary, the clinical significance o f the p.Ile73Val variant is uncertain. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 30, 2019

This missense variant replaces isoleucine with valine at codon 73 of the ACTC1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the ACTC1 protein (p.Ile73Val). This variant is present in population databases (rs750951965, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 32815737). ClinVar contains an entry for this variant (Variation ID: 228429). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. 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. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Uncertain

0.18

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.16

Cadd

Pathogenic

Dann

Benign

0.97

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.55

REVEL

Pathogenic

0.69

Sift4G

Benign

0.12

Polyphen

0.0040

Vest4

0.46

MutPred

0.65

Loss of sheet (P = 0.1158);

MVP

0.97

MPC

1.4

ClinPred

0.46

GERP RS

5.5

Varity_R

0.43

gMVP

0.90

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over