Genetic Variant ACTN3:c.1277-126T>C (chr11-66559110-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001104.4(ACTN3):c.1277-126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,045,904 control chromosomes in the GnomAD database, including 19,047 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3342 hom., cov: 32)

Exomes 𝑓: 0.18 ( 15705 hom. )

Consequence

ACTN3
NM_001104.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.685

Publications

27 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.1277-126T>C		intron_variant	Intron 11 of 20	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3 link	c.1406-126T>C		intron_variant	Intron 11 of 20		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ACTN3	ENST00000513398.2 link	c.1277-126T>C	intron_variant	Intron 11 of 20	1	NM_001104.4	ENSP00000426797.1
ENSG00000250105	ENST00000504911.1 link	n.336A>G	non_coding_transcript_exon_variant	Exon 2 of 2	3
ACTN3	ENST00000502692.5 link	c.1406-126T>C	intron_variant	Intron 11 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30643

AN:

151864

Hom.:

3340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.278

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.172

GnomAD4 exome

AF:

0.184

AC:

164545

AN:

893922

Hom.:

15705

Cov.:

AF XY:

0.184

AC XY:

80194

AN XY:

436394

show subpopulations

African (AFR)

AF:

0.281

AC:

5287

AN:

18808

American (AMR)

AF:

0.0907

AC:

1080

AN:

11908

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

1986

AN:

13724

East Asian (EAS)

AF:

0.155

AC:

4257

AN:

27482

South Asian (SAS)

AF:

0.189

AC:

5530

AN:

29246

European-Finnish (FIN)

AF:

0.212

AC:

8769

AN:

41278

Middle Eastern (MID)

AF:

0.143

AC:

361

AN:

2520

European-Non Finnish (NFE)

AF:

0.184

AC:

130488

AN:

710964

Other (OTH)

AF:

0.179

AC:

6787

AN:

37992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

6575

13150

19726

26301

32876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4770

9540

14310

19080

23850

<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:

0.202

AC:

30667

AN:

151982

Hom.:

3342

Cov.:

AF XY:

0.201

AC XY:

14959

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.278

AC:

11524

AN:

41434

American (AMR)

AF:

0.119

AC:

1816

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

465

AN:

3468

East Asian (EAS)

AF:

0.175

AC:

901

AN:

5160

South Asian (SAS)

AF:

0.160

AC:

772

AN:

4828

European-Finnish (FIN)

AF:

0.224

AC:

2362

AN:

10564

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.180

AC:

12243

AN:

67934

Other (OTH)

AF:

0.170

AC:

358

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1245

2490

3734

4979

6224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.178

Hom.:

10732

Bravo

AF:

0.197

Asia WGS

AF:

0.152

AC:

529

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.8

(source)

DANN

Benign

0.39

PhyloP100

-0.69

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

Computational scores

Splicing

Publications

Other links and lift over