rs727504399

Variant names:

• chr15-34794733-C-T
• rs727504399
• NM_005159.5:c.76G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005159.5(ACTC1):​c.76G>A​(p.Asp26Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,138 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D26E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.12
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 15-34794733-C-T is Pathogenic according to our data. Variant chr15-34794733-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177917.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	NM_005159.5	MANE Select	c.76G>A	p.Asp26Asn	missense	Exon 2 of 7	NP_005150.1
	ACTC1	NM_001406482.1		c.76G>A	p.Asp26Asn	missense	Exon 1 of 6	NP_001393411.1
	ACTC1	NM_001406483.1		c.76G>A	p.Asp26Asn	missense	Exon 2 of 7	NP_001393412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.76G>A	p.Asp26Asn	missense	Exon 2 of 7	ENSP00000290378.4
	ACTC1	ENST00000713613.1		c.76G>A	p.Asp26Asn	missense	Exon 2 of 8	ENSP00000518909.1
	ACTC1	ENST00000713610.1		c.76G>A	p.Asp26Asn	missense	Exon 2 of 7	ENSP00000518905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249618 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726892

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 11 Pathogenic:2

Aug 02, 2024

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>A (p.Asp26Asn) ACTC1 variant has been reported in our laboratory in a 67-year-old patient with diagnosis of hypertrophic cardiomyopathy. Father (sudden death 30y) and paternal grandmother (sudden death 50y). In our Hospital, it has been reported in another family with hypertrophic cardiomyopathy with positive segregation. This variant is present in population databases (gnomAD allele frequency 0.0000006198). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 27532257, 30600190]. ClinVar contains an entry for this variant (Variation ID: 117917). In silico analysis (CADD, Revel) supports that this missense variant has a deleterious effect on protein structure/function. In summary, c.76G>A (p.Asp26Asn) ACTC1 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity in this family and having been widely described in relation to the patient´s phenotype.

Nov 27, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.74 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000177917). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 26 of the ACTC1 protein (p.Asp26Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ACTC1-related conditions and hypertrophic cardiomyopathy (PMID: 27532257, 30600190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177917). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTC1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

not specified Uncertain:1

Feb 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

not provided Uncertain:1

Jul 11, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp26Asn (GAT>AAT):c.76 G>A in exon 2 of the ACTC1 gene (NM_005159.4). The Asp26Asn variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp26Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid residue with a neutral, polar Asparagine residue at a position that is conserved across species. In silico analysis predicts Asp26Asn is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Asp26Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding residues of the ACTC1 gene have been reported in association with HCM, suggesting this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Asp26Asn is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.46
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.74
Sift4G	Uncertain	0.023	D
Polyphen		0.95	P
Vest4		0.43
MutPred		0.62		Loss of disorder (P = 0.1505)
MVP		0.92
MPC		1.7
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.84
gMVP		0.93
Mutation Taster		=27/73	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504399; hg19: chr15-35086934; COSMIC: COSV51757846; COSMIC: COSV51757846;