rs1671064

Variant names:

• chr11-66560202-G-A
• rs1671064
• NM_001104.4:c.1568G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.52
• Publications: 51 publications found

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]

ENSG00000250105 (HGNC:58248):

ACMG classification

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	c.1568G>A	p.Arg523Gln	missense_variant	Exon 14 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.1697G>A	p.Arg566Gln	missense_variant	Exon 14 of 21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.1568G>A	p.Arg523Gln	missense_variant	Exon 14 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.1697G>A	p.Arg566Gln	missense_variant	Exon 14 of 21	2		ENSP00000422007.1
ENSG00000250105	ENST00000504911.1	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.: 32

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

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.: 74 AF XY: 0.547 AC XY: 395601 AN XY: 723868

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

GnomAD4 genome AF: 0.612 AC: 93085 AN: 152068 Hom.: 29728 Cov.: 32 AF XY: 0.611 AC XY: 45386 AN XY: 74298

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

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

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.68
DEOGEN2	Benign	0.21	T;T
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	9.1e-7	T;T
PhyloP100		7.5
PrimateAI	Uncertain	0.63	T
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

Other links and lift over

dbSNP: rs1671064; hg19: chr11-66327673; COSMIC: COSV59748951; COSMIC: COSV59748951;