rs605428

Variant names:

• chr1-229434057-G-A
• rs605428
• NM_001100.4:c.-66C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_001100.4:c.-66C>T variant in ACTA1 is a variant which is located in the 5’-UTR. The population filtering allele frequency in gnomAD v4.1.0 is 0.7509 (31375/41396 alleles with 11881 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/CA10609269/MONDO:0100084/147

• Frequency:
  • Genomes: 𝑓 0.63 (30999 hom., cov: 34)
  • Exomes 𝑓: 0.57 (60 hom.)
• Consequence: ACTA1 NM_001100.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.237
• 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.-66C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.-66C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.-66C>T		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-60C>T		5_prime_UTR_variant	Exon 1 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95881 AN: 151662 Hom.: 30962 Cov.: 34

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.776

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.661

GnomAD4 exome AF: 0.568 AC: 200 AN: 352 Hom.: 60 Cov.: 0 AF XY: 0.576 AC XY: 160 AN XY: 278

African (AFR) AF: 0.833 AC: 5 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.333 AC: 4 AN: 12

South Asian (SAS) AF: 0.600 AC: 6 AN: 10

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.569 AC: 173 AN: 304

Other (OTH) AF: 0.643 AC: 9 AN: 14

GnomAD4 genome AF: 0.632 AC: 95975 AN: 151780 Hom.: 30999 Cov.: 34 AF XY: 0.628 AC XY: 46544 AN XY: 74164

African (AFR) AF: 0.758 AC: 31370 AN: 41390

American (AMR) AF: 0.657 AC: 10026 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2530 AN: 3464

East Asian (EAS) AF: 0.457 AC: 2348 AN: 5140

South Asian (SAS) AF: 0.656 AC: 3165 AN: 4828

European-Finnish (FIN) AF: 0.475 AC: 5006 AN: 10530

Middle Eastern (MID) AF: 0.776 AC: 225 AN: 290

European-Non Finnish (NFE) AF: 0.580 AC: 39358 AN: 67868

Other (OTH) AF: 0.661 AC: 1390 AN: 2104

Alfa AF: 0.602 Hom.: 5701

Bravo AF: 0.652

Asia WGS AF: 0.606 AC: 2108 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Actin accumulation myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alpha-actinopathy Benign:1

Aug 27, 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.-66C>T variant in ACTA1 is a variant which is located in the 5’-UTR. The population filtering allele frequency in gnomAD v4.1.0 is 0.7509 (31375/41396 alleles with 11881 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). -

Congenital myopathy with fiber type disproportion Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial restrictive cardiomyopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		0.24
PromoterAI		0.023	Neutral
Mutation Taster		=297/3	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: rs605428; hg19: chr1-229569804; COSMIC: COSV64204088;