rs1064794652

Positions:

• chr1-229432408-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000366684.7(ACTA1):​c.478G>A​(p.Gly160Ser) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G160C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 ENST00000366684.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.76

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 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000366684.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-229432408-C-A is described in Lovd as [Pathogenic].
• 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, 0.966
• PP5: Variant 1-229432408-C-T is Pathogenic according to our data. Variant chr1-229432408-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432408-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.478G>A	p.Gly160Ser	missense_variant	4/7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.478G>A	p.Gly160Ser	missense_variant	4/7	1	NM_001100.4	ENSP00000355645	P1
ACTA1	ENST00000366683.4	c.478G>A	p.Gly160Ser	missense_variant	4/7	5		ENSP00000355644
ACTA1	ENST00000684723.1	c.343G>A	p.Gly115Ser	missense_variant	3/6			ENSP00000508084

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Actin accumulation myopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly160 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 19562689), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 420707). This missense change has been observed in individual(s) with autosomal dominant ACTA1-related conditions (PMID: 25326635, 31724238). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 160 of the ACTA1 protein (p.Gly160Ser). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2016

The G160S variant in the ACTA1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a missense pathogenic variant at this same codon (G160C), as well as missense pathogenic variants in neighboring codons (D156N, H163D, V165L, V165M), have been reported in the Human Gene Mutation Database in association with ACTA1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G160S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G160S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G160S variant is a strong candidate for a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;T
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.021	D;T
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.84		Gain of disorder (P = 0.0864);Gain of disorder (P = 0.0864);
MVP		1.0
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064794652; hg19: chr1-229568155;