rs121909526

chr1-229432596-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001100.4(ACTA1):c.414C>G(p.Ile138Met) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I138N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.03

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001100.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-229432597-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128260.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACTA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 1-229432596-G-C is Pathogenic according to our data. Variant chr1-229432596-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18286.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-229432596-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4	c.414C>G	p.Ile138Met	missense_variant	3/7	ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA1	ENST00000366684.7	c.414C>G	p.Ile138Met	missense_variant	3/7	1	NM_001100.4	P1
ACTA1	ENST00000366683.4	c.414C>G	p.Ile138Met	missense_variant	3/7	5
ACTA1	ENST00000684723.1	c.279C>G	p.Ile93Met	missense_variant	2/6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Actin accumulation myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 138 of the ACTA1 protein (p.Ile138Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy and/or clinical features of autosomal dominant ACTA1-related conditions (PMID: 10838259, 11333380; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as I136M. ClinVar contains an entry for this variant (Variation ID: 18286). 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 not expected to disrupt ACTA1 protein function. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15226407, 23294764). This variant disrupts the p.Ile138 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 11333380, 19562689), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.80
Sift4G	Uncertain	0.051	T;T
Polyphen		0.14	B;.
Vest4		0.88
MutPred		0.80		Gain of phosphorylation at Y135 (P = 0.2011);Gain of phosphorylation at Y135 (P = 0.2011);
MVP		0.94
ClinPred		0.81	D
GERP RS		0.49
Varity_R		0.94
gMVP		0.91

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: rs121909526; hg19: chr1-229568343;