chr1-229432520-G-A

Variant names:

• chr1-229432520-G-A
• rs569112604
• NM_001100.4:c.454+36C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001100.4(ACTA1):​c.454+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,371,116 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: ACTA1 NM_001100.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• 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=-0.85).
• BP6: Variant 1-229432520-G-A is Benign according to our data. Variant chr1-229432520-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000819 (120/146500) while in subpopulation NFE AF = 0.00131 (86/65648). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD,AD,AR,Unknown gene

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.454+36C>T		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.454+36C>T		intron	N/A	ENSP00000355645.3
	ACTA1	ENST00000366683.4	TSL:5	c.454+36C>T		intron	N/A	ENSP00000355644.4
	ACTA1	ENST00000684723.1		c.319+36C>T		intron	N/A	ENSP00000508084.1

Frequencies

GnomAD3 genomes AF: 0.000820 AC: 120 AN: 146410 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000518

Gnomad AMI AF: 0.00229

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000885

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00148

GnomAD2 exomes AF: 0.00103 AC: 155 AN: 150756 AF XY: 0.00117

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.000982

Gnomad ASJ exome AF: 0.000341

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00132 AC: 1614 AN: 1224616 Hom.: 4 Cov.: 34 AF XY: 0.00136 AC XY: 827 AN XY: 606168

African (AFR) AF: 0.000173 AC: 5 AN: 28950

American (AMR) AF: 0.000717 AC: 26 AN: 36242

Ashkenazi Jewish (ASJ) AF: 0.0000945 AC: 2 AN: 21166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35556

South Asian (SAS) AF: 0.00162 AC: 113 AN: 69948

European-Finnish (FIN) AF: 0.0000230 AC: 1 AN: 43564

Middle Eastern (MID) AF: 0.00194 AC: 7 AN: 3614

European-Non Finnish (NFE) AF: 0.00150 AC: 1398 AN: 933926

Other (OTH) AF: 0.00120 AC: 62 AN: 51650

GnomAD4 genome AF: 0.000819 AC: 120 AN: 146500 Hom.: 0 Cov.: 25 AF XY: 0.000702 AC XY: 50 AN XY: 71264

African (AFR) AF: 0.000517 AC: 21 AN: 40636

American (AMR) AF: 0.0000670 AC: 1 AN: 14936

Ashkenazi Jewish (ASJ) AF: 0.000299 AC: 1 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4682

South Asian (SAS) AF: 0.000885 AC: 4 AN: 4522

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9524

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.00131 AC: 86 AN: 65648

Other (OTH) AF: 0.00146 AC: 3 AN: 2050

Alfa AF: 0.000819 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.81
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

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: rs569112604; hg19: chr1-229568267;