1-229431626-T-G

Variant names:

• chr1-229431626-T-G
• rs121909528
• NM_001100.4:c.1007A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2 PP3 PM2_Supporting PP4_Moderate PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1007A>C (NM_001100.4(ACTA1):c.1007A>C (p.Glu336Ala)) variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 336 (p.Glu336Ala). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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). The computational predictor REVEL gives a score of 0.874, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). At least one patient with this variant displayed cores and fiber type disproportion on muscle biopsy, which is highly specific for actin accumulation myopathy (PP4_Moderate, PMID:15520409). This variant has been reported in 5 individuals from one family with muscle weakness (PP1_Moderate; PMID:15520409). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP2, PP3, PP4_Moderate, PP1_Moderate (Congenital Myopathies VCEP Specifications Version 2.0; July 8, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA128033/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA1 NM_001100.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.22

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]

ENSG00000290037 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.1007A>C	p.Glu336Ala	missense_variant	Exon 7 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.1007A>C	p.Glu336Ala	missense_variant	Exon 7 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000684723.1	c.872A>C	p.Glu291Ala	missense_variant	Exon 6 of 6			ENSP00000508084.1
ACTA1	ENST00000366683.4	c.991-62A>C		intron_variant	Intron 6 of 6	5		ENSP00000355644.4
ENSG00000290037	ENST00000702606.1	n.261T>G		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Alpha-actinopathy Pathogenic:1

Jul 08, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1007A>C (NM_001100.4(ACTA1):c.1007A>C (p.Glu336Ala)) variant in ACTA1 is a missense variant predicted to cause substitution of glutamate by alanine at amino acid 336 (p.Glu336Ala). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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). The computational predictor REVEL gives a score of 0.874, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (PP3). At least one patient with this variant displayed cores and fiber type disproportion on muscle biopsy, which is highly specific for actin accumulation myopathy (PP4_Moderate, PMID: 15520409). This variant has been reported in 5 individuals from one family with muscle weakness (PP1_Moderate; PMID: 15520409). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP2, PP3, PP4_Moderate, PP1_Moderate (Congenital Myopathies VCEP Specifications Version 2.0; July 8, 2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.87
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.90	P;.
Vest4		0.88
MutPred		0.91		Gain of MoRF binding (P = 0.012);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.97
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: rs121909528; hg19: chr1-229567373;