rs605428

chr1-229434057-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001100.4(ACTA1):c.-66C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,132 control chromosomes in the GnomAD database, including 31,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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 criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.237

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-229434057-G-A is Benign according to our data. Variant chr1-229434057-G-A is described in ClinVar as [Benign]. Clinvar id is 296062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229434057-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4	c.-66C>T		5_prime_UTR_variant	1/7	ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA1	ENST00000366684.7	c.-66C>T		5_prime_UTR_variant	1/7	1	NM_001100.4	P1
ACTA1	ENST00000366683.4	c.-66C>T		5_prime_UTR_variant	1/7	5
ACTA1	ENST00000684723.1	c.-60C>T		5_prime_UTR_variant	1/6

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

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.: 34 AF XY: 0.628 AC XY: 46544 AN XY: 74164

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Congenital myopathy with fiber type disproportion 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Familial restrictive cardiomyopathy 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
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

Other links and lift over

dbSNP: rs605428; hg19: chr1-229569804; COSMIC: COSV64204088;