15-34791137-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_005159.5(ACTC1):c.967G>A(p.Ala323Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,606,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ACTC1
NM_005159.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.90

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 Likely_pathogenic. Variant got 7 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, 10 uncertain in NM_005159.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-34791136-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180771.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=1}.

PP2

Missense variant where missense usually causes diseases, ACTC1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTC1	NM_005159.5 linkuse as main transcript	c.967G>A	p.Ala323Thr	missense_variant	6/7	ENST00000290378.6
GJD2-DT	NR_120329.1 linkuse as main transcript	n.299+13706C>T		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.967G>A	p.Ala323Thr	missense_variant	6/7	1	NM_005159.5	P1
GJD2-DT	ENST00000671663.1 linkuse as main transcript	n.95-19359C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249522

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134742

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454470

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721996

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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	Aug 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2022	This variant is present in population databases (rs771011464, gnomAD 0.003%). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1023541). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 323 of the ACTC1 protein (p.Ala323Thr). -

Hypertrophic cardiomyopathy 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Sep 14, 2022

The ACTC1 c.967G>A variant is classified as a VUS (PM2, PP3) The ACTC1 c.967G>A variant is a single nucleotide change in exon 6/7 of the ACTC1 gene, which is predicted to change the amino acid alanine at position 323 in the protein to threonine. The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het in 152044 sequenced alleles) (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs771011464), is reported as Uncertain significance by other diagnostic laboratories (ClinVar #1023541) and is not reported in HGMD. Different changes to this same amino acid have been reported in HGMD and ClinVar (p.Ala323Val/Ser/Pro) as variants of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

CardioboostCm

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.89

Sift4G

Uncertain

0.038

Polyphen

0.73

Vest4

0.80

MutPred

0.76

Gain of phosphorylation at A323 (P = 0.0635);

MVP

0.97

MPC

2.8

ClinPred

0.77

GERP RS

5.5

Varity_R

0.66

gMVP

0.95

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