NM_001104.4:c.2327A>G

Variant names:

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

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.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).

• 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
• Publications: 53 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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001104.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN3	NM_001104.4	MANE Select	c.2327A>G	p.Gln776Arg	missense	Exon 19 of 21	NP_001095.2
	ACTN3	NM_001258371.3		c.2456A>G	p.Gln819Arg	missense	Exon 19 of 21	NP_001245300.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN3	ENST00000513398.2	TSL:1 MANE Select	c.2327A>G	p.Gln776Arg	missense	Exon 19 of 21	ENSP00000426797.1
	ACTN3	ENST00000502692.5	TSL:2	c.2456A>G	p.Gln819Arg	missense	Exon 19 of 21	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

GnomAD2 exomes AF: 0.533 AC: 132907 AN: 249310 AF XY: 0.533

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 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

African (AFR) AF: 0.804 AC: 26912 AN: 33480

American (AMR) AF: 0.344 AC: 15366 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14482 AN: 26134

East Asian (EAS) AF: 0.514 AC: 20395 AN: 39698

South Asian (SAS) AF: 0.427 AC: 36843 AN: 86258

European-Finnish (FIN) AF: 0.673 AC: 35898 AN: 53312

Middle Eastern (MID) AF: 0.537 AC: 3090 AN: 5758

European-Non Finnish (NFE) AF: 0.554 AC: 616323 AN: 1111824

Other (OTH) AF: 0.552 AC: 33302 AN: 60364

GnomAD4 genome AF: 0.612 AC: 92863 AN: 151850 Hom.: 29593 Cov.: 30 AF XY: 0.611 AC XY: 45314 AN XY: 74202

African (AFR) AF: 0.792 AC: 32785 AN: 41392

American (AMR) AF: 0.445 AC: 6785 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1902 AN: 3466

East Asian (EAS) AF: 0.534 AC: 2747 AN: 5142

South Asian (SAS) AF: 0.418 AC: 2009 AN: 4808

European-Finnish (FIN) AF: 0.688 AC: 7276 AN: 10574

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37578 AN: 67904

Other (OTH) AF: 0.576 AC: 1214 AN: 2106

Alfa AF: 0.568 Hom.: 105877

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 v4.9

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
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	9.4e-7	T
PhyloP100		3.7
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	1.0	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

Other links and lift over

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