chr1-229431913-C-CG

Position:

• chr1-229431913-C-CG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_001100.4(ACTA1):c.809-13dup variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.2123 (1318/5930) in the Middle Eastern population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The c.809-13dup is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147047/MONDO:0100084/169

• Frequency:
  • Genomes: 𝑓 0.15 (1722 hom., cov: 29)
  • Exomes 𝑓: 0.16 (18917 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.306

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 Benign. Variant got -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.809-12dupC		intron_variant		ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.809-12dupC		intron_variant		1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.809-12dupC		intron_variant		5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.674-12dupC		intron_variant				ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22005 AN: 151436 Hom.: 1724 Cov.: 29

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.128 AC: 29474 AN: 230878 Hom.: 2285 AF XY: 0.132 AC XY: 16566 AN XY: 125518

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.0982

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.0992

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.159 AC: 232485 AN: 1459620 Hom.: 18917 Cov.: 34 AF XY: 0.160 AC XY: 116192 AN XY: 725836

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.145 AC: 22003 AN: 151552 Hom.: 1722 Cov.: 29 AF XY: 0.144 AC XY: 10649 AN XY: 74072

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.176

Alfa AF: 0.107 Hom.: 214

Asia WGS AF: 0.137 AC: 475 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2013	- -

Actin accumulation myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Alpha-actinopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The NM_001100.4(ACTA1):c.809-13dup variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.2123 (1318/5930) in the Middle Eastern population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The c.809-13dup is an intronic variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). In summary, this variant meets the criteria to be classified as benign for alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). -

Congenital myopathy with fiber type disproportion Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nemaline myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2016

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201427429; hg19: chr1-229567660;