NM_005159.5:c.903A>C

Variant names:

• chr15-34791201-T-G
• rs138347995
• NM_005159.5:c.903A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005159.5(ACTC1):​c.903A>C​(p.Leu301Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L301L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTC1 NM_005159.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.903A>C	p.Leu301Phe	missense	Exon 6 of 7	NP_005150.1
	ACTC1	NM_001406482.1		c.903A>C	p.Leu301Phe	missense	Exon 5 of 6	NP_001393411.1
	ACTC1	NM_001406483.1		c.903A>C	p.Leu301Phe	missense	Exon 6 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.903A>C	p.Leu301Phe	missense	Exon 6 of 7	ENSP00000290378.4
	ACTC1	ENST00000713613.1		c.1014A>C	p.Leu338Phe	missense	Exon 7 of 8	ENSP00000518909.1
	ACTC1	ENST00000713610.1		c.903A>C	p.Leu301Phe	missense	Exon 6 of 7	ENSP00000518905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251480 AF XY: 0.00000736

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: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		0.19
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.76
Sift4G	Uncertain	0.012	D
Polyphen		0.53	P
Vest4		0.62
MutPred		0.67		Gain of catalytic residue at L301 (P = 0.0986)
MVP		1.0
MPC		2.8
ClinPred		0.98	D
GERP RS		0.56
Varity_R		0.77
gMVP		0.98
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs138347995; hg19: chr15-35083402;