chr11-66560624-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001104.4(ACTN3):​c.1729C>T​(p.Arg577*) 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 Conflicting classifications of pathogenicity,Affects (no stars). 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_001104.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity; Affects no assertion criteria provided P:2 B:1 O:1
• Conservation: PhyloP100: 1.34

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.1858C>T	p.Arg620*	stop_gained	Exon 15 of 21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.1729C>T	p.Arg577*	stop_gained	Exon 15 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.1858C>T	p.Arg620*	stop_gained	Exon 15 of 21	2		ENSP00000422007.1
ENSG00000250105	ENST00000504911.1	n.-240G>A		upstream_gene_variant		3

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

Gnomad4 AFR exome AF: 0.156 AC: 5239 AN: 33480

Gnomad4 AMR exome AF: 0.651 AC: 29090 AN: 44712

Gnomad4 ASJ exome AF: 0.449 AC: 11729 AN: 26134

Gnomad4 EAS exome AF: 0.486 AC: 19312 AN: 39700

Gnomad4 SAS exome AF: 0.573 AC: 49397 AN: 86258

Gnomad4 FIN exome AF: 0.324 AC: 17223 AN: 53126

Gnomad4 NFE exome AF: 0.441 AC: 490044 AN: 1111826

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.170 AC: 0.170491 AN: 0.170491

Gnomad4 AMR AF: 0.546 AC: 0.545764 AN: 0.545764

Gnomad4 ASJ AF: 0.455 AC: 0.455017 AN: 0.455017

Gnomad4 EAS AF: 0.466 AC: 0.465631 AN: 0.465631

Gnomad4 SAS AF: 0.583 AC: 0.582988 AN: 0.582988

Gnomad4 FIN AF: 0.310 AC: 0.310384 AN: 0.310384

Gnomad4 NFE AF: 0.442 AC: 0.442225 AN: 0.442225

Gnomad4 OTH AF: 0.412 AC: 0.411932 AN: 0.411932

Alfa AF: 0.418 Hom.: 43300

Bravo AF: 0.382

ClinVar

Significance: Conflicting classifications of pathogenicity; Affects

Submissions summary: Pathogenic:2 Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

INCREASED COLD TOLERANCE Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sprinting performance Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ACTININ, ALPHA-3 POLYMORPHISM Benign:1

Mar 01, 2008

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Actn3 deficiency Other:1

Mar 01, 2008

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1815739; hg19: chr11-66328095;