11-66562261-A-G

Variant names:

• chr11-66562261-A-G
• rs540874
• NM_001104.4:c.2327A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.61 (29593 hom., cov: 30)
  • Exomes 𝑓: 0.55 (224066 hom.)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.67

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]

ACMG classification

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.2327A>G	p.Gln776Arg	missense_variant	Exon 19 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.2456A>G	p.Gln819Arg	missense_variant	Exon 19 of 21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.2327A>G	p.Gln776Arg	missense_variant	Exon 19 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.2456A>G	p.Gln819Arg	missense_variant	Exon 19 of 21	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92763 AN: 151730 Hom.: 29542 Cov.: 30

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

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.: 66 AF XY: 0.547 AC XY: 397433 AN XY: 727058

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.: 30 AF XY: 0.611 AC XY: 45314 AN XY: 74202

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: 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	0.058
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.21	T;T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	9.4e-7	T;T
PrimateAI	Uncertain	0.63	T
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

Other links and lift over

dbSNP: rs540874; hg19: chr11-66329732; COSMIC: COSV59747900; COSMIC: COSV59747900;