rs531419880

Variant names:

• chr1-229431173-C-CT
• rs531419880
• ENST00000684723.1:c.*325dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000684723.1(ACTA1):​c.*325dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 400,268 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: ACTA1 ENST00000684723.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.60
• 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

ENSG00000290037 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-229431173-C-CT is Benign according to our data. Variant chr1-229431173-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 1212858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0039 (594/152332) while in subpopulation NFE AF = 0.00353 (240/68024). AF 95% confidence interval is 0.00316. There are 7 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 SD,AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.*325_*326insA		downstream_gene_variant		ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000684723.1	c.*325dupA		3_prime_UTR_variant	Exon 6 of 6			ENSP00000508084.1
ACTA1	ENST00000366684.7	c.*325dupA		downstream_gene_variant		1	NM_001100.4	ENSP00000355645.3
ENSG00000290037	ENST00000702606.2	n.-193_-192insT		upstream_gene_variant
ACTA1	ENST00000366683.4	c.*325dupA		downstream_gene_variant		5		ENSP00000355644.4

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152214 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00313 AC: 777 AN: 247936 Hom.: 7 AF XY: 0.00292 AC XY: 391 AN XY: 133690

African (AFR) AF: 0.000850 AC: 6 AN: 7060

American (AMR) AF: 0.00155 AC: 19 AN: 12242

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 91 AN: 6578

East Asian (EAS) AF: 0.00 AC: 0 AN: 11804

South Asian (SAS) AF: 0.000868 AC: 36 AN: 41498

European-Finnish (FIN) AF: 0.0105 AC: 123 AN: 11732

Middle Eastern (MID) AF: 0.00105 AC: 1 AN: 954

European-Non Finnish (NFE) AF: 0.00330 AC: 472 AN: 142996

Other (OTH) AF: 0.00222 AC: 29 AN: 13072

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152332 Hom.: 7 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74500

African (AFR) AF: 0.000673 AC: 28 AN: 41580

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00325

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs531419880; hg19: chr1-229566920;