1-229431913-C-CG

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BA1BP7

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

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.306

Publications

3 publications found

Variant links:

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

ACTA1 links:

ENSG00000290037 (HGNC:):

ENSG00000290037 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.809-12dupC		intron_variant	Intron 5 of 6	ENST00000366684.7	NP_001091.1	P68133

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACTA1	ENST00000366684.7 link	c.809-12_809-11insC	intron_variant	Intron 5 of 6	1	NM_001100.4	ENSP00000355645.3	P68133
ACTA1	ENST00000366683.4 link	c.809-12_809-11insC	intron_variant	Intron 5 of 6	5		ENSP00000355644.4	A6NL76
ACTA1	ENST00000684723.1 link	c.674-12_674-11insC	intron_variant	Intron 4 of 5			ENSP00000508084.1	A0A804HKV3
ENSG00000290037	ENST00000702606.2 link	n.52_53insG	downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22005

AN:

151436

Hom.:

1724

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.128

AC:

29474

AN:

230878

AF XY:

0.132

show subpopulations

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 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.:

AF XY:

0.160

AC XY:

116192

AN XY:

725836

show subpopulations

African (AFR)

AF:

0.112

AC:

3725

AN:

33408

American (AMR)

AF:

0.128

AC:

5695

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

7666

AN:

26078

East Asian (EAS)

AF:

0.155

AC:

6129

AN:

39640

South Asian (SAS)

AF:

0.155

AC:

13358

AN:

86206

European-Finnish (FIN)

AF:

0.118

AC:

6288

AN:

53110

Middle Eastern (MID)

AF:

0.221

AC:

1247

AN:

5638

European-Non Finnish (NFE)

AF:

0.161

AC:

178739

AN:

1110642

Other (OTH)

AF:

0.160

AC:

9638

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

11715

23429

35144

46858

58573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6432

12864

19296

25728

32160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.145

AC:

22003

AN:

151552

Hom.:

1722

Cov.:

AF XY:

0.144

AC XY:

10649

AN XY:

74072

show subpopulations

African (AFR)

AF:

0.115

AC:

4721

AN:

41134

American (AMR)

AF:

0.134

AC:

2039

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1039

AN:

3468

East Asian (EAS)

AF:

0.155

AC:

794

AN:

5118

South Asian (SAS)

AF:

0.140

AC:

675

AN:

4816

European-Finnish (FIN)

AF:

0.117

AC:

1239

AN:

10574

Middle Eastern (MID)

AF:

0.243

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.160

AC:

10856

AN:

67888

Other (OTH)

AF:

0.176

AC:

370

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

841

1682

2524

3365

4206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Actin accumulation myopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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(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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 26, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial restrictive cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over