rs397517073

Variant names:

• chr15-34791254-T-A
• rs397517073
• NM_005159.5:c.850A>T
• ACTC1 p.Ile284Phe

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_005159.5(ACTC1):​c.850A>T​(p.Ile284Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,772 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 Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I284I) has been classified as Likely benign. The gene ACTC1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 5.08
• Publications: 1 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

Specifications for ACTC1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_005159.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 15-34791254-T-A is Pathogenic according to our data. Variant chr15-34791254-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 45191.Status of the report is reviewed_by_expert_panel, 3 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	NM_005159.5	MANE Select	c.850A>T	p.Ile284Phe	missense	Exon 6 of 7	NP_005150.1	P68032
	ACTC1	NM_001406482.1		c.850A>T	p.Ile284Phe	missense	Exon 5 of 6	NP_001393411.1	P68032
	ACTC1	NM_001406483.1		c.850A>T	p.Ile284Phe	missense	Exon 6 of 7	NP_001393412.1	P68032

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTC1	ENST00000290378.6	TSL:1 MANE Select	c.850A>T	p.Ile284Phe	missense	Exon 6 of 7	ENSP00000290378.4	P68032
	ACTC1	ENST00000713613.1		c.961A>T	p.Ile321Phe	missense	Exon 7 of 8	ENSP00000518909.1	A0AAQ5BGG2
	ACTC1	ENST00000868408.1		c.856A>T	p.Ile286Phe	missense	Exon 6 of 7	ENSP00000538467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 11 (1)
-	1	-	Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.92
Sift4G	Pathogenic	0.0	D
Varity_R		0.96
gMVP		0.99
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397517073;

hg19: chr15-35083455;