15-34794799-C-T

Position:

• chr15-34794799-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005159.5(ACTC1):​c.10G>A​(p.Asp4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.17

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.10G>A	p.Asp4Asn	missense_variant	2/7	ENST00000290378.6	NP_005150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.10G>A	p.Asp4Asn	missense_variant	2/7	1	NM_005159.5	ENSP00000290378.4
ACTC1	ENST00000560563.2	n.116G>A		non_coding_transcript_exon_variant	2/6	2
GJD2-DT	ENST00000503496.6	n.300-15697C>T		intron_variant		2
GJD2-DT	ENST00000671663.1	n.95-15697C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250544 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135562

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: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461104 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

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: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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	Jul 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4 of the ACTC1 protein (p.Asp4Asn). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 538810). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 21, 2022

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2019

The p.D4N variant (also known as c.10G>A), located in coding exon 1 of the ACTC1 gene, results from a G to A substitution at nucleotide position 10. The aspartic acid at codon 4 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.20
CardioboostCm	Benign	0.047
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.048
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.38
Sift4G	Benign	0.088	T
Polyphen		0.0020	B
Vest4		0.57
MutPred		0.37		Loss of disorder (P = 0.1555);
MVP		0.80
MPC		1.6
ClinPred		0.78	D
GERP RS		4.2
Varity_R		0.46
gMVP		0.89

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

Other links and lift over

dbSNP: rs730880408; hg19: chr15-35087000; COSMIC: COSV51757480; COSMIC: COSV51757480;