rs397517069

Positions:

• chr15-34794802-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The ENST00000290378.6(ACTC1):​c.7G>C​(p.Asp3His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D3D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 ENST00000290378.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.7G>C	p.Asp3His	missense_variant	2/7	ENST00000290378.6	NP_005150.1
GJD2-DT	NR_120329.1	n.300-15694C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.7G>C	p.Asp3His	missense_variant	2/7	1	NM_005159.5	ENSP00000290378	P1
GJD2-DT	ENST00000671663.1	n.95-15694C>G		intron_variant, non_coding_transcript_variant
ACTC1	ENST00000560563.2	n.113G>C		non_coding_transcript_exon_variant	2/6	2
GJD2-DT	ENST00000503496.6	n.300-15694C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2014

The Asp3His variant in ACTC1 has not been previously reported in any other famil ies with cardimyopathy and was absent from large population studies. Computation al prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of th e Asp3His variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
CardioboostCm	Uncertain	0.10
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.62
Sift4G	Uncertain	0.0020	D
Polyphen		0.17	B
Vest4		0.81
MutPred		0.38		Loss of sheet (P = 0.0817);
MVP		0.97
MPC		1.9
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.49
gMVP		0.88

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: rs397517069; hg19: chr15-35087003;