Variant 11-66562261-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001104.4(ACTN3):c.2327A>G(p.Gln776Arg) variant causes a missense change. The variant allele was found at a frequency of 0.555 in 1,613,402 control chromosomes in the GnomAD database, including 253,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.61 ( 29593 hom., cov: 30)

Exomes 𝑓: 0.55 ( 224066 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3758257E-7).

BP6

Variant 11-66562261-A-G is Benign according to our data. Variant chr11-66562261-A-G is described in ClinVar as [Benign]. Clinvar id is 3060488.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN3	NM_001104.4 linkuse as main transcript	c.2327A>G	p.Gln776Arg	missense_variant	19/21	ENST00000513398.2
ACTN3	NM_001258371.3 linkuse as main transcript	c.2456A>G	p.Gln819Arg	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN3	ENST00000513398.2 linkuse as main transcript	c.2327A>G	p.Gln776Arg	missense_variant	19/21	1	NM_001104.4	P1
ACTN3	ENST00000502692.5 linkuse as main transcript	c.2456A>G	p.Gln819Arg	missense_variant	19/21	2

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92763

AN:

151730

Hom.:

29542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.792

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.549

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.688

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.582

GnomAD3 exomes

AF:

0.533

AC:

132907

AN:

249310

Hom.:

37399

AF XY:

0.533

AC XY:

72107

AN XY:

135244

show subpopulations

Gnomad AFR exome

AF:

0.790

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.562

Gnomad EAS exome

AF:

0.552

Gnomad SAS exome

AF:

0.419

Gnomad FIN exome

AF:

0.679

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.529

GnomAD4 exome

AF:

0.549

AC:

802611

AN:

1461552

Hom.:

224066

Cov.:

AF XY:

0.547

AC XY:

397433

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.804

Gnomad4 AMR exome

AF:

0.344

Gnomad4 ASJ exome

AF:

0.554

Gnomad4 EAS exome

AF:

0.514

Gnomad4 SAS exome

AF:

0.427

Gnomad4 FIN exome

AF:

0.673

Gnomad4 NFE exome

AF:

0.554

Gnomad4 OTH exome

AF:

0.552

GnomAD4 genome

AF:

0.612

AC:

92863

AN:

151850

Hom.:

29593

Cov.:

AF XY:

0.611

AC XY:

45314

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.792

Gnomad4 AMR

AF:

0.445

Gnomad4 ASJ

AF:

0.549

Gnomad4 EAS

AF:

0.534

Gnomad4 SAS

AF:

0.418

Gnomad4 FIN

AF:

0.688

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.576

Alfa

AF:

0.562

Hom.:

50325

Bravo

AF:

0.602

TwinsUK

AF:

0.555

AC:

2057

ALSPAC

AF:

0.554

AC:

2136

ESP6500AA

AF:

0.786

AC:

3316

ESP6500EA

AF:

0.550

AC:

4656

ExAC

AF:

0.542

AC:

65594

Asia WGS

AF:

0.498

AC:

1731

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ACTN3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

0.058

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.21

T;T

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

9.4e-7

T;T

PrimateAI

Uncertain

0.63

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.022

GERP RS

5.7

Varity_R

0.048

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over