Genetic Variant NM_001104.4:c.1568G>A (chr11-66560202-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001104.4(ACTN3):c.1568G>A(p.Arg523Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,608,268 control chromosomes in the GnomAD database, including 252,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. R523R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.61 ( 29728 hom., cov: 32)

Exomes 𝑓: 0.55 ( 223067 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.52

Publications

51 publications found

Variant links:

Genes affected

ACTN3 (HGNC:165): (actinin alpha 3) This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status. [provided by RefSeq, Feb 2014]

ACTN3 links:

ENSG00000250105 (HGNC:58248):

ENSG00000250105 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.1066215E-7).

BP6

Variant 11-66560202-G-A is Benign according to our data. Variant chr11-66560202-G-A is described in ClinVar as [Benign]. Clinvar id is 3059413.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.1568G>A	p.Arg523Gln	missense_variant	Exon 14 of 21	ENST00000513398.2	NP_001095.2	Q08043B4DZQ2
ACTN3	NM_001258371.3 link	c.1697G>A	p.Arg566Gln	missense_variant	Exon 14 of 21		NP_001245300.2	Q08043A0A087WSZ2B4DZQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACTN3	ENST00000513398.2 link	c.1568G>A	p.Arg523Gln	missense_variant	Exon 14 of 21	1	NM_001104.4	ENSP00000426797.1	Q08043
ACTN3	ENST00000502692.5 link	c.1697G>A	p.Arg566Gln	missense_variant	Exon 14 of 21	2		ENSP00000422007.1	A0A087WSZ2
ENSG00000250105	ENST00000504911.1 link	n.183C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.612

AC:

92985

AN:

151952

Hom.:

29675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.795

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.545

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.688

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.581

GnomAD2 exomes

AF:

0.534

AC:

126656

AN:

237270

AF XY:

0.534

show subpopulations

Gnomad AFR exome

AF:

0.799

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.560

Gnomad EAS exome

AF:

0.555

Gnomad FIN exome

AF:

0.680

Gnomad NFE exome

AF:

0.559

Gnomad OTH exome

AF:

0.527

GnomAD4 exome

AF:

0.549

AC:

799593

AN:

1456200

Hom.:

223067

Cov.:

AF XY:

0.547

AC XY:

395601

AN XY:

723868

show subpopulations

African (AFR)

AF:

0.809

AC:

27033

AN:

33410

American (AMR)

AF:

0.344

AC:

15130

AN:

43922

Ashkenazi Jewish (ASJ)

AF:

0.551

AC:

14357

AN:

26040

East Asian (EAS)

AF:

0.514

AC:

20266

AN:

39452

South Asian (SAS)

AF:

0.427

AC:

36481

AN:

85346

European-Finnish (FIN)

AF:

0.673

AC:

35535

AN:

52782

Middle Eastern (MID)

AF:

0.535

AC:

3079

AN:

5752

European-Non Finnish (NFE)

AF:

0.554

AC:

614591

AN:

1109402

Other (OTH)

AF:

0.551

AC:

33121

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

22983

45965

68948

91930

114913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17262

34524

51786

69048

86310

<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:

0.612

AC:

93085

AN:

152068

Hom.:

29728

Cov.:

AF XY:

0.611

AC XY:

45386

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.796

AC:

33008

AN:

41474

American (AMR)

AF:

0.445

AC:

6801

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

1892

AN:

3470

East Asian (EAS)

AF:

0.533

AC:

2745

AN:

5152

South Asian (SAS)

AF:

0.416

AC:

2005

AN:

4822

European-Finnish (FIN)

AF:

0.688

AC:

7266

AN:

10568

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.553

AC:

37584

AN:

67962

Other (OTH)

AF:

0.576

AC:

1217

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1743

3486

5228

6971

8714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.571

Hom.:

85372

Bravo

AF:

0.603

TwinsUK

AF:

0.555

AC:

2058

ALSPAC

AF:

0.555

AC:

2140

ESP6500AA

AF:

0.793

AC:

3385

ESP6500EA

AF:

0.553

AC:

4706

ExAC

AF:

0.536

AC:

64730

Asia WGS

AF:

0.497

AC:

1729

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACTN3-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.21

T;T

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.66

T;T

MetaRNN

Benign

9.1e-7

T;T

PhyloP100

7.5

PrimateAI

Uncertain

0.63

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.071

GERP RS

4.8

Varity_R

0.067

gMVP

0.077

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

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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