rs605428

Positions:

chr1-229434057-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BA1BP7

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

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.237

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4 linkuse as main transcript	c.-66C>T		5_prime_UTR_variant	1/7	ENST00000366684.7	NP_001091.1	P68133

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACTA1	ENST00000366684.7 linkuse as main transcript	c.-66C>T	5_prime_UTR_variant	1/7	1	NM_001100.4	ENSP00000355645.3	P68133
ACTA1	ENST00000366683.4 linkuse as main transcript	c.-66C>T	5_prime_UTR_variant	1/7	5		ENSP00000355644.4	A6NL76
ACTA1	ENST00000684723.1 linkuse as main transcript	c.-60C>T	5_prime_UTR_variant	1/6			ENSP00000508084.1	A0A804HKV3

Frequencies

GnomAD3 genomes

AF:

0.632

AC:

95881

AN:

151662

Hom.:

30962

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.576

AC XY:

160

AN XY:

278

show subpopulations

Gnomad4 AFR exome

AF:

0.833

Gnomad4 EAS exome

AF:

0.333

Gnomad4 SAS exome

AF:

0.600

Gnomad4 NFE exome

AF:

0.569

Gnomad4 OTH exome

AF:

0.643

GnomAD4 genome

AF:

0.632

AC:

95975

AN:

151780

Hom.:

30999

Cov.:

AF XY:

0.628

AC XY:

46544

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.758

Gnomad4 AMR

AF:

0.657

Gnomad4 ASJ

AF:

0.730

Gnomad4 EAS

AF:

0.457

Gnomad4 SAS

AF:

0.656

Gnomad4 FIN

AF:

0.475

Gnomad4 NFE

AF:

0.580

Gnomad4 OTH

AF:

0.661

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -

Actin accumulation myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 27, 2024

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Familial restrictive cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over