1-229431720-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3_StrongPVS1_Strong

This summary comes from the ClinGen Evidence Repository: The variant c.990+1G>T in ACTA1 occurs within the canonical splice donor site (+1) of intron 6. It is predicted to cause skipping of biologically-relevant-exon resulting in an out of frame deletion. However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met). This variant has been reported in trans with a pathogenic variant in two probands with nemaline myopathy (PMID:19562689, LOVD (https://www.dmd.nl/)), and homozygous in one proband with nemaline myopathy (https://helda.helsinki.fi/handle/10138/157180) which meets PM3_Strong. In summary, the variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Strong (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1442746/MONDO:0100084/169

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ACTA1
NM_001100.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 7.68

Publications

1 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: Pathogenic. The variant received 8 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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.990+1G>T		splice_donor_variant, intron_variant	Intron 6 of 6	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ACTA1	ENST00000366684.7 link	c.990+1G>T	splice_donor_variant, intron_variant	Intron 6 of 6	1	NM_001100.4	ENSP00000355645.3
ENSG00000290037	ENST00000702606.2 link	n.355C>A	non_coding_transcript_exon_variant	Exon 1 of 1
ACTA1	ENST00000366683.4 link	c.990+1G>T	splice_donor_variant, intron_variant	Intron 6 of 6	5		ENSP00000355644.4
ACTA1	ENST00000684723.1 link	c.855+1G>T	splice_donor_variant, intron_variant	Intron 5 of 5			ENSP00000508084.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251344

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111996

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000282

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Actin accumulation myopathy

Pathogenic:2

Aug 30, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 24, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in the last intron (intron 6) of the ACTA1 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in an individual affected with severe nemaline myopathy. It was reported to occur in trans with a pathogenic variant (p.Tyr190*) and to be inherited in an autosomal recessive manner (PMID: 19562689). This variant has also been reported in trans with another pathogenic variant (p.Ala146Profs*46) in a second individual affected with nemaline myopathy (http://www.dmd.nl/nmdb). Truncating mutations in ACTA1 are not known to cause autosomal dominant forms of nemaline myopathy (PMID: 12921789,Â¬â€ 19562689). Although donor and acceptor splice site variants are typically truncating (PMID: 16199547) and truncating variants in ACTA1 are known to be pathogenic (PMID: 19562689), the pathogenicity of this donor splice site variant in the last intron is not conclusive due to the uncertain impact on mRNA splicing and protein function.Â¬â€ Without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:2

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16199547, 12921789, 25525159, 31589614, 19562689) -

Alpha-actinopathy

Pathogenic:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The variant c.990+1G>T in ACTA1 occurs within the canonical splice donor site (+1) of intron 6. It is predicted to cause skipping of biologically-relevant-exon resulting in an out of frame deletion. However, it is predicted to escape nonsense mediated decay and remove >10% of the protein (PVS1_Strong). The highest minor allele frequency in gnomAD v4.1.0 is 0.00001883 (31/1180028 alleles) in the European (non-Finnish) population (no population codes met). This variant has been reported in trans with a pathogenic variant in two probands with nemaline myopathy (PMID:19562689, LOVD (https://www.dmd.nl/)), and homozygous in one proband with nemaline myopathy (https://helda.helsinki.fi/handle/10138/157180) which meets PM3_Strong. In summary, the variant meets the criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Strong (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

PhyloP100

7.7

GERP RS

3.6

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: 2

DS_DL_spliceai

1.0

Position offset: 1

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