rs605430

Variant names:

• chr1-229434056-A-G
• rs605430
• NM_001100.4:c.-65T>C

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.-65T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,086 control chromosomes in the GnomAD database, including 31,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31003 hom., cov: 34)
  • Exomes 𝑓: 0.57 (61 hom.)
• Consequence: ACTA1 NM_001100.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.581
• Publications: 7 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=-0.63).
• BP6: Variant 1-229434056-A-G is Benign according to our data. Variant chr1-229434056-A-G is described in ClinVar as Benign. ClinVar VariationId is 296060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4	c.-65T>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000366684.7	NP_001091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA1	ENST00000366684.7	c.-65T>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_001100.4	ENSP00000355645.3
ACTA1	ENST00000366683.4	c.-65T>C		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000355644.4
ACTA1	ENST00000684723.1	c.-59T>C		5_prime_UTR_variant	Exon 1 of 6			ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95886 AN: 151622 Hom.: 30966 Cov.: 34

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.776

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.572 AC: 198 AN: 346 Hom.: 61 Cov.: 0 AF XY: 0.581 AC XY: 158 AN XY: 272

African (AFR) AF: 0.833 AC: 5 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.333 AC: 4 AN: 12

South Asian (SAS) AF: 0.600 AC: 6 AN: 10

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.571 AC: 169 AN: 296

Other (OTH) AF: 0.643 AC: 9 AN: 14

GnomAD4 genome AF: 0.633 AC: 95980 AN: 151740 Hom.: 31003 Cov.: 34 AF XY: 0.628 AC XY: 46547 AN XY: 74144

African (AFR) AF: 0.758 AC: 31371 AN: 41378

American (AMR) AF: 0.657 AC: 10026 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2530 AN: 3464

East Asian (EAS) AF: 0.458 AC: 2348 AN: 5132

South Asian (SAS) AF: 0.656 AC: 3168 AN: 4830

European-Finnish (FIN) AF: 0.475 AC: 5006 AN: 10528

Middle Eastern (MID) AF: 0.776 AC: 225 AN: 290

European-Non Finnish (NFE) AF: 0.580 AC: 39358 AN: 67850

Other (OTH) AF: 0.662 AC: 1391 AN: 2102

Alfa AF: 0.599 Hom.: 3401

Bravo AF: 0.652

Asia WGS AF: 0.606 AC: 2108 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 03, 2018

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

- -

Actin accumulation myopathy 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. -

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	-0.63
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		0.58
PromoterAI		-0.17	Neutral
Mutation Taster		=297/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs605430; hg19: chr1-229569803; COSMIC: COSV64203106;