rs527621

Positions:

• chr1-229432484-T-G

Variant summary

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

The ENST00000366684.7(ACTA1):​c.455-53A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,565,742 control chromosomes in the GnomAD database, including 780,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (72854 hom., cov: 19)
  • Exomes 𝑓: 1.0 (708030 hom.)
• Consequence: ACTA1 ENST00000366684.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.38

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=-0.91).
• BP6: Variant 1-229432484-T-G is Benign according to our data. Variant chr1-229432484-T-G is described in ClinVar as [Benign]. Clinvar id is 676564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432484-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.455-53A>C		intron_variant		ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.455-53A>C		intron_variant		1	NM_001100.4	ENSP00000355645	P1
ACTA1	ENST00000366683.4	c.455-53A>C		intron_variant		5		ENSP00000355644
ACTA1	ENST00000684723.1	c.320-53A>C		intron_variant				ENSP00000508084

Frequencies

GnomAD3 genomes AF: 0.998 AC: 145848 AN: 146076 Hom.: 72810 Cov.: 19

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.968

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.997

GnomAD4 exome AF: 0.999 AC: 1417811 AN: 1419578 Hom.: 708030 Cov.: 41 AF XY: 0.999 AC XY: 701196 AN XY: 702164

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 0.970

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.996

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.998 AC: 145936 AN: 146164 Hom.: 72854 Cov.: 19 AF XY: 0.998 AC XY: 70813 AN XY: 70922

Gnomad4 AFR AF: 1.00

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 0.968

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.997

Alfa AF: 0.999 Hom.: 9236

Bravo AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Actin accumulation myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Progressive scapulohumeroperoneal distal myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Congenital myopathy with fiber type disproportion Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.1
DANN	Benign	0.42

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: rs527621; hg19: chr1-229568231;