rs1815739

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received -9 classification points (ACMG Germline Pathogenicity v2019): 0P and 9B. BA1BP6

The NM_001104.4(ACTN3):c.1729C>T (p.Arg577*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.439 (AC=708,445) in the gnomAD database across 1,613,426 control chromosomes, including 161,361 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.644. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: 𝑓 0.38 ( 12141 hom., cov: 32)

Exomes 𝑓: 0.45 ( 149220 hom. )

Consequence

ACTN3
NM_001104.4 stop_gained

Scores

Clinical Significance

Benign criteria provided, single submitter P:2B:2O:1

Conservation

PhyloP100: 1.34

Publications

572 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:

ACTN3-AS1 (HGNC:58248):

ACTN3-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001104.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -9 points.

BP6

ClinVar 1-star benign with significant pathogenic submissions — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s), conflicting pathogenic submissions present (B/LB: 2, P/LP: 2).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6443 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001104.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN3	NM_001104.4	MANE Select	c.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	NP_001095.2	Q08043
	ACTN3	NM_001258371.3		c.1858C>T	p.Arg620*	stop_gained	Exon 15 of 21	NP_001245300.2	A0A087WSZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN3	ENST00000513398.2	TSL:1 MANE Select	c.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	ENSP00000426797.1	Q08043
ACTN3	ENST00000502692.5	TSL:2	c.1858C>T	p.Arg620*	stop_gained	Exon 15 of 21	ENSP00000422007.1	A0A087WSZ2
ACTN3	ENST00000968415.1		c.1738C>T	p.Arg580*	stop_gained	Exon 15 of 21	ENSP00000638474.1

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

57028

AN:

151932

Hom.:

12131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.171

Gnomad AMI

AF:

0.566

Gnomad AMR

AF:

0.546

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.466

Gnomad SAS

AF:

0.584

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.442

Gnomad OTH

AF:

0.407

GnomAD4 exome

AF:

0.446

AC:

651404

AN:

1461372

Hom.:

149220

Cov.:

AF XY:

0.449

AC XY:

326110

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.156

AC:

5239

AN:

33480

American (AMR)

AF:

0.651

AC:

29090

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

11729

AN:

26134

East Asian (EAS)

AF:

0.486

AC:

19312

AN:

39700

South Asian (SAS)

AF:

0.573

AC:

49397

AN:

86258

European-Finnish (FIN)

AF:

0.324

AC:

17223

AN:

53126

Middle Eastern (MID)

AF:

0.463

AC:

2671

AN:

5768

European-Non Finnish (NFE)

AF:

0.441

AC:

490044

AN:

1111826

Other (OTH)

AF:

0.442

AC:

26699

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

23597

47193

70790

94386

117983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14890

29780

44670

59560

74450

<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:

0.375

AC:

57041

AN:

152054

Hom.:

12141

Cov.:

AF XY:

0.377

AC XY:

28028

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.170

AC:

7073

AN:

41486

American (AMR)

AF:

0.546

AC:

8336

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1578

AN:

3468

East Asian (EAS)

AF:

0.466

AC:

2398

AN:

5150

South Asian (SAS)

AF:

0.583

AC:

2810

AN:

4820

European-Finnish (FIN)

AF:

0.310

AC:

3282

AN:

10574

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.442

AC:

30058

AN:

67970

Other (OTH)

AF:

0.412

AC:

870

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1745

3490

5236

6981

8726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

564

1128

1692

2256

2820

<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:

0.418

Hom.:

43300

Bravo

AF:

0.382

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.527

AC:

64652

AN:

122568

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.416

AC:

3729

AN:

8960

Hom.:

798

ABraOM SABE-WGS-1171

AF:

0.401

AC:

939

AN:

2342

Hom.:

185

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ACTININ, ALPHA-3 POLYMORPHISM (1)

INCREASED COLD TOLERANCE (1)

not specified (1)

Sprinting performance (1)

Actn3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

PhyloP100

1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over