11-66560624-C-T

Variant names:

• chr11-66560624-C-T
• rs1815739
• NM_001104.4:c.1729C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001258371.3(ACTN3):​c.1858C>T​(p.Arg620*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,426 control chromosomes in the GnomAD database, including 161,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.38 (12141 hom., cov: 32)
  • Exomes 𝑓: 0.45 (149220 hom.)
• Consequence: ACTN3 NM_001258371.3 stop_gained
• Clinical Significance: Benign criteria provided, single submitter P:2 B:2 O:1
• Conservation: PhyloP100: 1.34
• Publications: 552 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]

ACTN3-AS1 (HGNC:58248):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-66560624-C-T is Benign according to our data. Variant chr11-66560624-C-T is described in ClinVar as Benign. ClinVar VariationId is 18312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258371.3. 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.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	NP_001095.2
	ACTN3	NM_001258371.3		c.1858C>T	p.Arg620*	stop_gained	Exon 15 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.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	ENSP00000426797.1
	ACTN3	ENST00000502692.5	TSL:2	c.1858C>T	p.Arg620*	stop_gained	Exon 15 of 21	ENSP00000422007.1
	ACTN3	ENST00000968415.1		c.1738C>T	p.Arg580*	stop_gained	Exon 15 of 21	ENSP00000638474.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57028 AN: 151932 Hom.: 12131 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.446 AC: 651404 AN: 1461372 Hom.: 149220 Cov.: 64 AF XY: 0.449 AC XY: 326110 AN XY: 726946

African (AFR) AF: 0.156 AC: 5239 AN: 33480

American (AMR) AF: 0.651 AC: 29090 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 11729 AN: 26134

East Asian (EAS) AF: 0.486 AC: 19312 AN: 39700

South Asian (SAS) AF: 0.573 AC: 49397 AN: 86258

European-Finnish (FIN) AF: 0.324 AC: 17223 AN: 53126

Middle Eastern (MID) AF: 0.463 AC: 2671 AN: 5768

European-Non Finnish (NFE) AF: 0.441 AC: 490044 AN: 1111826

Other (OTH) AF: 0.442 AC: 26699 AN: 60368

GnomAD4 genome AF: 0.375 AC: 57041 AN: 152054 Hom.: 12141 Cov.: 32 AF XY: 0.377 AC XY: 28028 AN XY: 74302

African (AFR) AF: 0.170 AC: 7073 AN: 41486

American (AMR) AF: 0.546 AC: 8336 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1578 AN: 3468

East Asian (EAS) AF: 0.466 AC: 2398 AN: 5150

South Asian (SAS) AF: 0.583 AC: 2810 AN: 4820

European-Finnish (FIN) AF: 0.310 AC: 3282 AN: 10574

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30058 AN: 67970

Other (OTH) AF: 0.412 AC: 870 AN: 2112

Alfa AF: 0.418 Hom.: 43300

Bravo AF: 0.382

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ACTININ, ALPHA-3 POLYMORPHISM (1)
1	-	-	INCREASED COLD TOLERANCE (1)
-	-	1	not specified (1)
1	-	-	Sprinting performance (1)
-	-	-	Actn3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	37
PhyloP100		1.3
Vest4		0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1815739; hg19: chr11-66328095;