rs569112604

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.01

Publications

0 publications found

Variant links:

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

ACTA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA1	NM_001100.4 link	c.454+36C>T		intron_variant	Intron 3 of 6	ENST00000366684.7	NP_001091.1	P68133

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACTA1	ENST00000366684.7 link	c.454+36C>T	intron_variant	Intron 3 of 6	1	NM_001100.4	ENSP00000355645.3	P68133
ACTA1	ENST00000366683.4 link	c.454+36C>T	intron_variant	Intron 3 of 6	5		ENSP00000355644.4	A6NL76
ACTA1	ENST00000684723.1 link	c.319+36C>T	intron_variant	Intron 2 of 5			ENSP00000508084.1	A0A804HKV3

Frequencies

GnomAD3 genomes

AF:

0.000820

AC:

120

AN:

146410

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00136

AC XY:

827

AN XY:

606168

show subpopulations

African (AFR)

AF:

0.000173

AC:

AN:

28950

American (AMR)

AF:

0.000717

AC:

AN:

36242

Ashkenazi Jewish (ASJ)

AF:

0.0000945

AC:

AN:

21166

East Asian (EAS)

AF:

0.00

AC:

AN:

35556

South Asian (SAS)

AF:

0.00162

AC:

113

AN:

69948

European-Finnish (FIN)

AF:

0.0000230

AC:

AN:

43564

Middle Eastern (MID)

AF:

0.00194

AC:

AN:

3614

European-Non Finnish (NFE)

AF:

0.00150

AC:

1398

AN:

933926

Other (OTH)

AF:

0.00120

AC:

AN:

51650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000819

AC:

120

AN:

146500

Hom.:

Cov.:

AF XY:

0.000702

AC XY:

AN XY:

71264

show subpopulations

African (AFR)

AF:

0.000517

AC:

AN:

40636

American (AMR)

AF:

0.0000670

AC:

AN:

14936

Ashkenazi Jewish (ASJ)

AF:

0.000299

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4682

South Asian (SAS)

AF:

0.000885

AC:

AN:

4522

European-Finnish (FIN)

AF:

0.000105

AC:

AN:

9524

Middle Eastern (MID)

AF:

0.00357

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

65648

Other (OTH)

AF:

0.00146

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000819

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.5

(source)

DANN

Benign

0.81

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over