rs121909532

Variant names:

• chr1-229432393-C-T
• rs121909522
• NM_001100.4:c.493G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-229432393-C-T
• chr1-229432393-C-G
• chr1-229432393-C-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PP1_Moderate PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.493G>A variant in ACTA1 is a missense variant predicted to cause substitution of valine by methionine at amino acid 165 (legacy nomenclature: p.Val163Met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). In vitro studies in C2C12 myoblasts showed that V165M formed intranuclear actin aggregates with low levels of cytoplasmic aggregates, indicating that this variant impacts protein function. These oblong intranuclear aggregates closely resembled intranuclear bodies observed in muscle samples from patients with intranuclear myopathy. Additionally, Drosophila heterozygous for V165M show that V165M can severely affect Z-disc assembly and the stability of the sarcomere. Heterozygous V165M Drosophila presented with zebra bodies, Z-rings, and intranuclear rods (PS3; PMID:15198992, 17705262, 23294764). This variant has been reported in 1 proband with intranuclear rod myopathy confirmed by biopsy (PP4_Moderate; PMID:12921789). The variant has been reported to segregate with nemaline myopathy in 2 affected family members from 1 family (PP1_Moderate; PMID:12921789). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS3, PP4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP2 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA258144/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.76
• Publications: 9 publications found

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]

ACTA1 Gene-Disease associations (from GenCC):

• alpha-actinopathy

  Inheritance: AD, AR, SD Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 2a, typical, autosomal dominant

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital myopathy with excess of thin filaments

  Inheritance: SD Classification: DEFINITIVE Submitted by: Illumina
• congenital myopathy 2c, severe infantile, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive scapulohumeroperoneal distal myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• zebra body myopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	NM_001100.4	MANE Select	c.493G>A	p.Val165Met	missense	Exon 4 of 7	NP_001091.1	P68133

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	ENST00000366684.7	TSL:1 MANE Select	c.493G>A	p.Val165Met	missense	Exon 4 of 7	ENSP00000355645.3	P68133
	ACTA1	ENST00000871224.1		c.493G>A	p.Val165Met	missense	Exon 3 of 6	ENSP00000541283.1
	ACTA1	ENST00000871225.1		c.493G>A	p.Val165Met	missense	Exon 4 of 7	ENSP00000541284.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Actin accumulation myopathy (2)
2	-	-	Alpha-actinopathy (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.96
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.92		Gain of loop (P = 0.1069)
MVP		0.99
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909522; hg19: chr1-229568140; COSMIC: COSV64203141;