rs144658220

chr1-229432956-G-T

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.129+31C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,613,690 control chromosomes in the GnomAD database, including 500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (104 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (396 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.284

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=-0.86).
• BP6: Variant 1-229432956-G-T is Benign according to our data. Variant chr1-229432956-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 257442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432956-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4	c.129+31C>A		intron_variant		ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA1	ENST00000366684.7	c.129+31C>A		intron_variant		1	NM_001100.4	P1
ACTA1	ENST00000366683.4	c.129+31C>A		intron_variant		5
ACTA1	ENST00000684723.1	c.-6-76C>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2506 AN: 152180 Hom.: 99 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0770

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0202 AC: 4968 AN: 245466 Hom.: 266 AF XY: 0.0164 AC XY: 2188 AN XY: 133686

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00612

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.00742 AC: 10841 AN: 1461392 Hom.: 396 Cov.: 38 AF XY: 0.00696 AC XY: 5062 AN XY: 727002

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00591

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00817

GnomAD4 genome AF: 0.0165 AC: 2520 AN: 152298 Hom.: 104 Cov.: 33 AF XY: 0.0173 AC XY: 1288 AN XY: 74464

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0779

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0100 Hom.: 7

Bravo AF: 0.0232

Asia WGS AF: 0.0120 AC: 40 AN: 3478

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.3
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs144658220; hg19: chr1-229568703;