rs144658220

Variant names:

• chr1-229432956-G-T
• rs144658220
• NM_001100.4:c.129+31C>A

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.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:4
• Conservation: PhyloP100: -0.284
• Publications: 0 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=-0.86).
• BP6: Variant 1-229432956-G-T is Benign according to our data. Variant chr1-229432956-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.129+31C>A		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.129+31C>A		intron_variant	Intron 2 of 6	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.129+31C>A		intron_variant	Intron 2 of 6	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-6-76C>A		intron_variant	Intron 1 of 5			ENSP00000508084.1

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

GnomAD2 exomes AF: 0.0202 AC: 4968 AN: 245466 AF XY: 0.0164

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 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

African (AFR) AF: 0.0201 AC: 674 AN: 33474

American (AMR) AF: 0.117 AC: 5227 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00591 AC: 510 AN: 86222

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53298

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00342 AC: 3799 AN: 1111816

Other (OTH) AF: 0.00817 AC: 493 AN: 60362

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

African (AFR) AF: 0.0223 AC: 927 AN: 41582

American (AMR) AF: 0.0779 AC: 1193 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4826

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68006

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 01, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.52
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144658220; hg19: chr1-229568703;