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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	NM_001100.4	MANE Select	c.130-5T>C		splice_region intron	N/A	NP_001091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	ENST00000366684.7	TSL:1 MANE Select	c.130-5T>C		splice_region intron	N/A	ENSP00000355645.3
	ACTA1	ENST00000366683.4	TSL:5	c.130-5T>C		splice_region intron	N/A	ENSP00000355644.4
	ACTA1	ENST00000684723.1		c.-6-5T>C		splice_region intron	N/A	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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Actin accumulation myopathy (2)
-	-	2	not provided (2)
-	-	1	Congenital myopathy with fiber type disproportion (1)
-	-	1	Familial restrictive cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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;