rs11803533

Variant names:

• chr1-229432885-A-G
• rs11803533
• NM_001100.4:c.130-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-229432885-A-G
• chr1-229432885-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001100.4(ACTA1):​c.130-5T>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00004295
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.545
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• alpha-actinopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 2a, typical, autosomal dominant

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital myopathy with excess of thin filaments

  Inheritance: SD Classification: DEFINITIVE Submitted by: Illumina
• congenital myopathy 2c, severe infantile, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive scapulohumeroperoneal distal myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• rigid spine syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• zebra body myopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.130-5T>C		splice_region_variant, intron_variant	Intron 2 of 6	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.130-5T>C		splice_region_variant, intron_variant	Intron 2 of 6	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.130-5T>C		splice_region_variant, intron_variant	Intron 2 of 6	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-6-5T>C		splice_region_variant, intron_variant	Intron 1 of 5			ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39900 AN: 151896 Hom.: 6571 Cov.: 32

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

GnomAD2 exomes AF: 0.208 AC: 52169 AN: 250470 AF XY: 0.202

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 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.: 41 AF XY: 0.184 AC XY: 134003 AN XY: 727176

African (AFR) AF: 0.479 AC: 16052 AN: 33478

American (AMR) AF: 0.270 AC: 12072 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 8480 AN: 26132

East Asian (EAS) AF: 0.156 AC: 6207 AN: 39700

South Asian (SAS) AF: 0.179 AC: 15455 AN: 86254

European-Finnish (FIN) AF: 0.116 AC: 6182 AN: 53396

Middle Eastern (MID) AF: 0.262 AC: 1511 AN: 5766

European-Non Finnish (NFE) AF: 0.173 AC: 192264 AN: 1111952

Other (OTH) AF: 0.203 AC: 12286 AN: 60394

GnomAD4 genome AF: 0.263 AC: 39976 AN: 152016 Hom.: 6596 Cov.: 32 AF XY: 0.259 AC XY: 19248 AN XY: 74354

African (AFR) AF: 0.468 AC: 19398 AN: 41458

American (AMR) AF: 0.262 AC: 4008 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.160 AC: 821 AN: 5130

South Asian (SAS) AF: 0.167 AC: 807 AN: 4818

European-Finnish (FIN) AF: 0.115 AC: 1221 AN: 10608

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11695 AN: 67926

Other (OTH) AF: 0.277 AC: 585 AN: 2110

Alfa AF: 0.226 Hom.: 2820

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Actin accumulation myopathy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myopathy with fiber type disproportion Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial restrictive cardiomyopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.85
CADD	Benign	2.4
DANN	Benign	0.45
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11803533; hg19: chr1-229568632; COSMIC: COSV64203448;