Variant rs1671064 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.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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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 criteria provided, single submitter B:1

Conservation

PhyloP100: 7.52

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:

(HGNC:):

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=9.1066215E-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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
ACTN3	NM_001104.4 linkuse as main transcript	c.1568G>A	p.Arg523Gln	missense_variant	14/21	ENST00000513398.2
ACTN3	NM_001258371.3 linkuse as main transcript	c.1697G>A	p.Arg566Gln	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ACTN3	ENST00000513398.2 linkuse as main transcript	c.1568G>A	p.Arg523Gln	missense_variant	14/21	1	NM_001104.4	P1
	ENST00000504911.1 linkuse as main transcript	n.183C>T		non_coding_transcript_exon_variant	1/2	3
ACTN3	ENST00000502692.5 linkuse as main transcript	c.1697G>A	p.Arg566Gln	missense_variant	14/21	2

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

GnomAD3 exomes

AF:

0.534

AC:

126656

AN:

237270

Hom.:

35477

AF XY:

0.534

AC XY:

68981

AN XY:

129208

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 SAS exome

AF:

0.421

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

Gnomad4 AFR exome

AF:

0.809

Gnomad4 AMR exome

AF:

0.344

Gnomad4 ASJ exome

AF:

0.551

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:

0.551

GnomAD4 genome

AF:

0.612

AC:

93085

AN:

152068

Hom.:

29728

Cov.:

AF XY:

0.611

AC XY:

45386

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.796

Gnomad4 AMR

AF:

0.445

Gnomad4 ASJ

AF:

0.545

Gnomad4 EAS

AF:

0.533

Gnomad4 SAS

AF:

0.416

Gnomad4 FIN

AF:

0.688

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.576

Alfa

AF:

0.569

Hom.:

34417

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: 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

0.061

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

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

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

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