rs11803533

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001100.4(ACTA1):c.130-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,613,794 control chromosomes in the GnomAD database, including 33,901 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6596 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27305 hom. )

Consequence

ACTA1
NM_001100.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004295

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.545

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-229432885-A-G is Benign according to our data. Variant chr1-229432885-A-G is described in ClinVar as [Benign]. Clinvar id is 93547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432885-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA1	NM_001100.4 linkuse as main transcript	c.130-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366684.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
ACTA1	ENST00000366684.7 linkuse as main transcript	c.130-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_001100.4	P1
ACTA1	ENST00000366683.4 linkuse as main transcript	c.130-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5
ACTA1	ENST00000684723.1 linkuse as main transcript	c.-6-5T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39900

AN:

151896

Hom.:

6571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.261

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.277

GnomAD3 exomes

AF:

0.208

AC:

52169

AN:

250470

Hom.:

6207

AF XY:

0.202

AC XY:

27325

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.467

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.330

Gnomad EAS exome

AF:

0.176

Gnomad SAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.175

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.185

AC:

270509

AN:

1461778

Hom.:

27305

Cov.:

AF XY:

0.184

AC XY:

134003

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.479

Gnomad4 AMR exome

AF:

0.270

Gnomad4 ASJ exome

AF:

0.325

Gnomad4 EAS exome

AF:

0.156

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.116

Gnomad4 NFE exome

AF:

0.173

Gnomad4 OTH exome

AF:

0.203

GnomAD4 genome

AF:

0.263

AC:

39976

AN:

152016

Hom.:

6596

Cov.:

AF XY:

0.259

AC XY:

19248

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.262

Gnomad4 ASJ

AF:

0.331

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.167

Gnomad4 FIN

AF:

0.115

Gnomad4 NFE

AF:

0.172

Gnomad4 OTH

AF:

0.277

Alfa

AF:

0.220

Hom.:

2542

Bravo

AF:

0.287

Asia WGS

AF:

0.198

AC:

687

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.190

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.130-5T>C in intron 2 of ACTA1: This variant is not expected to have clinical s ignificance because it has been identified in 45.0% (1983/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs11803533). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -

Actin accumulation myopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Congenital myopathy with fiber type disproportion

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Mar 03, 2015

- -

Familial restrictive cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

2.4

Dann

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000043

dbscSNV1_RF

Benign

0.024

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