rs59228224

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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: AR, AD 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

ENSG00000290037 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	NM_001100.4	MANE Select	c.809-35delG		intron	N/A	NP_001091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	ENST00000366684.7	TSL:1 MANE Select	c.809-35delG		intron	N/A	ENSP00000355645.3
	ACTA1	ENST00000366683.4	TSL:5	c.809-35delG		intron	N/A	ENSP00000355644.4
	ACTA1	ENST00000684723.1		c.674-35delG		intron	N/A	ENSP00000508084.1

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

GnomAD2 exomes AF: 0.146 AC: 31739 AN: 217818 AF XY: 0.143

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 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

African (AFR) AF: 0.279 AC: 9285 AN: 33314

American (AMR) AF: 0.255 AC: 11370 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7781 AN: 26026

East Asian (EAS) AF: 0.155 AC: 6138 AN: 39590

South Asian (SAS) AF: 0.162 AC: 13919 AN: 86120

European-Finnish (FIN) AF: 0.122 AC: 6459 AN: 52748

Middle Eastern (MID) AF: 0.227 AC: 1194 AN: 5262

European-Non Finnish (NFE) AF: 0.174 AC: 192811 AN: 1109620

Other (OTH) AF: 0.186 AC: 11163 AN: 60080

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

African (AFR) AF: 0.273 AC: 11235 AN: 41176

American (AMR) AF: 0.236 AC: 3592 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1056 AN: 3464

East Asian (EAS) AF: 0.158 AC: 793 AN: 5034

South Asian (SAS) AF: 0.151 AC: 720 AN: 4754

European-Finnish (FIN) AF: 0.121 AC: 1270 AN: 10500

Middle Eastern (MID) AF: 0.253 AC: 73 AN: 288

European-Non Finnish (NFE) AF: 0.173 AC: 11684 AN: 67682

Other (OTH) AF: 0.230 AC: 483 AN: 2104

Alfa AF: 0.118 Hom.: 267

Asia WGS AF: 0.162 AC: 561 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Alpha-actinopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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