1-229433100-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001100.4(ACTA1):c.16G>A(p.Glu6Lys) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.65

Genes affected

ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACTA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 1-229433100-C-T is Pathogenic according to our data. Variant chr1-229433100-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229433100-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4	c.16G>A	p.Glu6Lys	missense_variant	2/7	ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA1	ENST00000366684.7	c.16G>A	p.Glu6Lys	missense_variant	2/7	1	NM_001100.4	P1
ACTA1	ENST00000366683.4	c.16G>A	p.Glu6Lys	missense_variant	2/7	5
ACTA1	ENST00000684723.1	c.-6-220G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 6 of the ACTA1 protein (p.Glu6Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital fiber type disproportion, congenital myopathy, and/or nemaline myopathy (PMID: 19562689, 24642510, 26172852). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTA1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Progressive scapulohumeroperoneal distal myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 01, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP4,PP5. -

Congenital myopathy with fiber type disproportion Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.76
Sift4G	Benign	0.11	T;T
Polyphen		0.18	B;.
Vest4		0.92
MutPred		0.62		Gain of ubiquitination at E6 (P = 0.017);Gain of ubiquitination at E6 (P = 0.017);
MVP		0.97
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.99

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: rs367543048; hg19: chr1-229568847; COSMIC: COSV64204126;