1-229432190-G-T

Variant names:

• chr1-229432190-G-T
• NM_001100.4:c.617-5C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_Supporting PS4_Supporting PP1_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.617-5C>A variant in ACTA1 is an intronic variant in the 3’ non-canonical splice site of intron 4. This variant is predicted to create a cryptic splice site, and add one amino acid (Ala) translated from intron 4 to the mature protein, but the exact impact is unknown because no functional studies have been performed. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor SpliceAI gives a score of 1 predicting an acceptor gain, which is above the threshold of 0.5, evidence that correlates with impact to ACTA1 function (PP3). This variant has been reported in two families with myopathy without muscle biopsies and three adults with features of muscle weakness (PS4_Supporting; PMID:19562689, Invitae, SCV001556001.2, GeneDx, SCV001986137.1). The variant has been reported to segregate with myopathy in 2 affected family members from 1 family (PP1_Moderate, Invitae, SCV001556001.2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2499214555/MONDO:0100084/147

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA1 NM_001100.4 splice_region, intron
• Scores: Splicing: ADA: 0.9873
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: -0.521

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 Uncertain_significance. Variant got 5 ACMG points.

• PS4: 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.
• PP3: 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.617-5C>A		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.617-5C>A		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.617-5C>A		splice_region_variant, intron_variant	Intron 4 of 6	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.482-5C>A		splice_region_variant, intron_variant	Intron 3 of 5			ENSP00000508084.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Apr 19, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19562689) -

Aug 13, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Actin accumulation myopathy Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the ACTA1 gene. It does not directly change the encoded amino acid sequence of the ACTA1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant nemaline myopathy (PMID: 19562689; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1051987). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Alpha-actinopathy Uncertain:1

Aug 27, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.617-5C>A variant in ACTA1 is an intronic variant in the 3’ non-canonical splice site of intron 4. This variant is predicted to create a cryptic splice site, and add one amino acid (Ala) translated from intron 4 to the mature protein, but the exact impact is unknown because no functional studies have been performed. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor SpliceAI gives a score of 1 predicting an acceptor gain, which is above the threshold of 0.5, evidence that correlates with impact to ACTA1 function (PP3). This variant has been reported in two families with myopathy without muscle biopsies and three adults with features of muscle weakness (PS4_Supporting; PMID: 19562689, Invitae, SCV001556001.2, GeneDx, SCV001986137.1). The variant has been reported to segregate with myopathy in 2 affected family members from 1 family (PP1_Moderate, Invitae, SCV001556001.2). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Supporting, PP1_Moderate, PM2_Supporting, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	22
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-229567937;