rs59228224

Variant names:

• chr1-229431936-TC-T
• rs59228224
• NM_001100.4:c.809-35delG

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_001100.4:c.809-35del variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The population filtering allele frequency in gnomAD v4.1.0 is 0.2723 (20520/74490 alleles with 2805 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC 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, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147050/MONDO:0100084/169

• Frequency:
  • Genomes: 𝑓 0.21 (3438 hom., cov: 27)
  • Exomes 𝑓: 0.18 (23911 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -1.26

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 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 rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.809-35delG		intron_variant	Intron 5 of 6	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.809-35delG		intron_variant	Intron 5 of 6	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.809-35delG		intron_variant	Intron 5 of 6	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.674-35delG		intron_variant	Intron 4 of 5			ENSP00000508084.1
ENSG00000290037	ENST00000702606.1	n.*98delC		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31071 AN: 151054 Hom.: 3427 Cov.: 27

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.146 AC: 31739 AN: 217818 Hom.: 3779 AF XY: 0.143 AC XY: 17036 AN XY: 119100

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.0920

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.178 AC: 260120 AN: 1457272 Hom.: 23911 Cov.: 29 AF XY: 0.178 AC XY: 128917 AN XY: 724270

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.206 AC: 31110 AN: 151166 Hom.: 3438 Cov.: 27 AF XY: 0.204 AC XY: 15036 AN XY: 73840

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.230

Alfa AF: 0.118 Hom.: 267

Asia WGS AF: 0.162 AC: 561 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Sep 13, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alpha-actinopathy Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001100.4:c.809-35del variant in ACTA1 is an intronic variant which is located in the 3’ non-canonical splice site of intron 5. The population filtering allele frequency in gnomAD v4.1.0 is 0.2723 (20520/74490 alleles with 2805 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold for BA1, and therefore meets this criterion (BA1). The results from the in silico predictor, SpliceAI, suggest that the variant does not impact ACTA1 function and it occurs at a nucleotide that is not conserved as shown by the UCSC 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, BP7 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs59228224; hg19: chr1-229567683; COSMIC: COSV64203079;