rs267606629

Positions:

• chr15-34790549-C-A
• chr15-34790549-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_005159.5(ACTC1):​c.997G>T​(p.Ala333Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A333P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-34790549-C-G is described in Lovd as [Pathogenic].
• 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, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTC1	NM_005159.5	c.997G>T	p.Ala333Ser	missense_variant	7/7	ENST00000290378.6	NP_005150.1
GJD2-DT	NR_120329.1	n.299+13118C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTC1	ENST00000290378.6	c.997G>T	p.Ala333Ser	missense_variant	7/7	1	NM_005159.5	ENSP00000290378	P1
GJD2-DT	ENST00000671663.1	n.95-19947C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000297 AC: 43 AN: 1448954 Hom.: 0 Cov.: 31 AF XY: 0.0000333 AC XY: 24 AN XY: 721016

Gnomad4 AFR exome AF: 0.0000909

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.0000781

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000292

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
CardioboostCm	Uncertain	0.77
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.88
Sift4G	Uncertain	0.038	D
Polyphen		0.069	B
Vest4		0.64
MutPred		0.88		Gain of disorder (P = 0.0448);
MVP		0.97
MPC		1.6
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-35082750;