rs121909523

Positions:

• chr1-229432020-T-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000366684.7(ACTA1):​c.782A>T​(p.Glu261Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,459,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ACTA1 ENST00000366684.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.17

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 17 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000366684.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA1. . Gene score misZ 4.5292 (greater than the threshold 3.09). Trascript score misZ 6.088 (greater than threshold 3.09). GenCC has associacion of gene with congenital myopathy with excess of thin filaments, nemaline myopathy 3, intermediate nemaline myopathy, typical nemaline myopathy, congenital fiber-type disproportion myopathy, severe congenital nemaline myopathy, rigid spine syndrome, zebra body myopathy, childhood-onset nemaline myopathy, congenital myopathy 2c, severe infantile, autosomal dominant, alpha-actinopathy, progressive scapulohumeroperoneal distal myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-229432020-T-A is Pathogenic according to our data. Variant chr1-229432020-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432020-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.782A>T	p.Glu261Val	missense_variant	5/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.782A>T	p.Glu261Val	missense_variant	5/7	1	NM_001100.4	ENSP00000355645	P1
ACTA1	ENST00000366683.4	c.782A>T	p.Glu261Val	missense_variant	5/7	5		ENSP00000355644
ACTA1	ENST00000684723.1	c.647A>T	p.Glu216Val	missense_variant	4/6			ENSP00000508084

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459368 Hom.: 0 Cov.: 34 AF XY: 0.00000689 AC XY: 5 AN XY: 725922

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 30, 2020	PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2023	Published functional studies demonstrate a damaging effect: abnormal protein folding (PMID: 15226407); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10508519, 26582918, 27535533, 24077912, 15226407) -

Actin accumulation myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15226407). 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. ClinVar contains an entry for this variant (Variation ID: 18283). This variant is also known as p.Glu259Val. This missense change has been observed in individual(s) with autosomal recessive nemaline myopathy (PMID: 10508519, 15236405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909523, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 261 of the ACTA1 protein (p.Glu261Val). -

Congenital myopathy with fiber type disproportion;C3711389:Actin accumulation myopathy;C4225181:Progressive scapulohumeroperoneal distal myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Congenital myopathy 2b, severe infantile, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1999

- -

ACTA1-related myopathies Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 08, 2019

The ACTA1 c.782A>T (p.Glu261Val) variant, also referred to as p.Glu259Val, is a missense variant that has been reported in two studies which describe three compound heterozygous individuals with severe, autosomal recessive, nemaline myopathy, including a pair of siblings (Nowak et al. 1999; Agrawal et al. 2004). In both studies, the p.Glu261Val variant was inherited from heterozygous, clinically-unaffected parents. The p.Glu261Val variant was absent from 100 control subjects and is reported at a frequency of 0.000065 in the European (Non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Costa et al. (2004) evaluated the effect of the variant on protein folding and found that the variant protein was not released from prefoldin and CCT nor did it associated with actin-monomer-binding proteins, indicating a defective protein. Based on rarity of the variant, its identification in multiple affected individuals in the literature, and its effect on protein function, the p.Glu261Val variant is classified as likely pathogenic for ACTA1-related myopathies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	5.5	H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.91
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.85
MutPred		0.93		Gain of catalytic residue at E261 (P = 0.2322);
MVP		1.0
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121909523; hg19: chr1-229567767;