rs527621

Variant names:

• chr1-229432484-T-G
• rs527621
• NM_001100.4:c.455-53A>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.455-53A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,565,742 control chromosomes in the GnomAD database, including 780,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (72854 hom., cov: 19)
  • Exomes 𝑓: 1.0 (708030 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.38
• Publications: 5 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=-0.91).
• BP6: Variant 1-229432484-T-G is Benign according to our data. Variant chr1-229432484-T-G is described in ClinVar as Benign. ClinVar VariationId is 676564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	NM_001100.4	MANE Select	c.455-53A>C		intron	N/A	NP_001091.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA1	ENST00000366684.7	TSL:1 MANE Select	c.455-53A>C		intron	N/A	ENSP00000355645.3
	ACTA1	ENST00000871224.1		c.455-53A>C		intron	N/A	ENSP00000541283.1
	ACTA1	ENST00000871225.1		c.455-53A>C		intron	N/A	ENSP00000541284.1

Frequencies

GnomAD3 genomes AF: 0.998 AC: 145848 AN: 146076 Hom.: 72810 Cov.: 19

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.968

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.997

GnomAD4 exome AF: 0.999 AC: 1417811 AN: 1419578 Hom.: 708030 Cov.: 41 AF XY: 0.999 AC XY: 701196 AN XY: 702164

African (AFR) AF: 1.00 AC: 32902 AN: 32906

American (AMR) AF: 0.999 AC: 42369 AN: 42402

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 23224 AN: 23950

East Asian (EAS) AF: 1.00 AC: 38903 AN: 38904

South Asian (SAS) AF: 0.996 AC: 79245 AN: 79558

European-Finnish (FIN) AF: 1.00 AC: 45095 AN: 45108

Middle Eastern (MID) AF: 0.990 AC: 3989 AN: 4030

European-Non Finnish (NFE) AF: 1.00 AC: 1093652 AN: 1094104

Other (OTH) AF: 0.997 AC: 58432 AN: 58616

GnomAD4 genome AF: 0.998 AC: 145936 AN: 146164 Hom.: 72854 Cov.: 19 AF XY: 0.998 AC XY: 70813 AN XY: 70922

African (AFR) AF: 1.00 AC: 39467 AN: 39478

American (AMR) AF: 0.999 AC: 14684 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 3288 AN: 3398

East Asian (EAS) AF: 1.00 AC: 4684 AN: 4684

South Asian (SAS) AF: 0.997 AC: 4407 AN: 4422

European-Finnish (FIN) AF: 1.00 AC: 9869 AN: 9872

Middle Eastern (MID) AF: 1.00 AC: 286 AN: 286

European-Non Finnish (NFE) AF: 0.999 AC: 66409 AN: 66476

Other (OTH) AF: 0.997 AC: 1954 AN: 1960

Alfa AF: 0.999 Hom.: 9236

Bravo AF: 0.999

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Actin accumulation myopathy (1)
-	-	1	Congenital myopathy with fiber type disproportion (1)
-	-	1	Progressive scapulohumeroperoneal distal myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.1
DANN	Benign	0.42
PhyloP100		-1.4
Mutation Taster		=6/94	disease causing

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: rs527621; hg19: chr1-229568231;