1-229431916-C-G

Variant names:

• chr1-229431916-C-G
• rs6673359
• NM_001100.4:c.809-14G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_001100.4:c.809-14G>C 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 0.4599 (34684/74748 alleles with 8023 homozygotes) in the African/African American population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (≥0.0025 for AR, ≥0.00000781 for AD) 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, BP4, BP7 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147048/MONDO:0100084/147

• Frequency:
  • Genomes: 𝑓 0.26 (6324 hom., cov: 31)
  • Exomes 𝑓: 0.18 (26047 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: 0.0150
• Publications: 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	NM_001100.4	MANE Select	c.809-14G>C		intron	N/A	NP_001091.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	ENST00000366684.7	TSL:1 MANE Select	c.809-14G>C		intron	N/A	ENSP00000355645.3
	ACTA1	ENST00000871224.1		c.809-14G>C		intron	N/A	ENSP00000541283.1
	ACTA1	ENST00000871225.1		c.809-14G>C		intron	N/A	ENSP00000541284.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39067 AN: 151590 Hom.: 6302 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.195 AC: 46476 AN: 238246 AF XY: 0.189

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.180 AC: 263407 AN: 1459812 Hom.: 26047 Cov.: 35 AF XY: 0.180 AC XY: 130595 AN XY: 725892

African (AFR) AF: 0.471 AC: 15737 AN: 33410

American (AMR) AF: 0.268 AC: 11960 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8417 AN: 26096

East Asian (EAS) AF: 0.156 AC: 6178 AN: 39646

South Asian (SAS) AF: 0.179 AC: 15441 AN: 86222

European-Finnish (FIN) AF: 0.121 AC: 6418 AN: 53108

Middle Eastern (MID) AF: 0.259 AC: 1455 AN: 5628

European-Non Finnish (NFE) AF: 0.167 AC: 185853 AN: 1110812

Other (OTH) AF: 0.198 AC: 11948 AN: 60244

GnomAD4 genome AF: 0.258 AC: 39139 AN: 151704 Hom.: 6324 Cov.: 31 AF XY: 0.254 AC XY: 18859 AN XY: 74148

African (AFR) AF: 0.458 AC: 18947 AN: 41338

American (AMR) AF: 0.258 AC: 3933 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1138 AN: 3466

East Asian (EAS) AF: 0.158 AC: 804 AN: 5104

South Asian (SAS) AF: 0.167 AC: 802 AN: 4802

European-Finnish (FIN) AF: 0.119 AC: 1259 AN: 10558

Middle Eastern (MID) AF: 0.302 AC: 87 AN: 288

European-Non Finnish (NFE) AF: 0.168 AC: 11391 AN: 67860

Other (OTH) AF: 0.275 AC: 579 AN: 2108

Alfa AF: 0.139 Hom.: 341

Bravo AF: 0.281

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Actin accumulation myopathy (2)
-	-	2	not provided (2)
-	-	1	Alpha-actinopathy (1)
-	-	1	Congenital myopathy with fiber type disproportion (1)
-	-	1	Familial restrictive cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		0.015
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: rs6673359; hg19: chr1-229567663;