rs398123565

Positions:

• chr1-229431916-C-CG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001100.4(ACTA1):​c.809-15dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,611,844 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (50 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.120

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 -16 ACMG points.

• BP6: Variant 1-229431916-C-CG is Benign according to our data. Variant chr1-229431916-C-CG is described in ClinVar as [Likely_benign]. Clinvar id is 93553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00398 (605/151834) while in subpopulation NFE AF= 0.00672 (456/67892). AF 95% confidence interval is 0.00621. There are 3 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.809-15dupC		intron_variant		ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.809-15dupC		intron_variant		1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.809-15dupC		intron_variant		5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.674-15dupC		intron_variant				ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 604 AN: 151720 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00661

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00670

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.00675 AC: 9854 AN: 1460010 Hom.: 50 Cov.: 35 AF XY: 0.00639 AC XY: 4641 AN XY: 726006

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00201

Gnomad4 NFE exome AF: 0.00827

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.00398 AC: 605 AN: 151834 Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 267 AN XY: 74216

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00672

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00484 Hom.: 0

Bravo AF: 0.00425

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 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, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2012	- -

Actin accumulation myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs398123565; hg19: chr1-229567663;