15-34790438-A-G

Position:

• chr15-34790438-A-G

Variant summary

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

The NM_005159.5(ACTC1):​c.1108T>C​(p.Ser370Pro) variant causes a missense change. 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. S370C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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 where missense usually causes diseases, ACTC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTC1	NM_005159.5	c.1108T>C	p.Ser370Pro	missense_variant	7/7	ENST00000290378.6
GJD2-DT	NR_120329.1	n.299+13007A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTC1	ENST00000290378.6	c.1108T>C	p.Ser370Pro	missense_variant	7/7	1	NM_005159.5	P1
GJD2-DT	ENST00000671663.1	n.95-20058A>G		intron_variant, non_coding_transcript_variant

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

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The p.S370P variant (also known as c.1108T>C), located in coding exon 6 of the ACTC1 gene, results from a T to C substitution at nucleotide position 1108. The serine at codon 370 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Uncertain	0.64
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.72
Sift4G	Uncertain	0.054	T
Polyphen		0.54	P
Vest4		0.75
MutPred		0.35		Gain of catalytic residue at P369 (P = 0.0107);
MVP		0.99
MPC		2.4
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-35082639;