Variant chr11-66560624-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001104.4(ACTN3):c.1729C>T(p.Arg577Ter) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity; Affects no assertion criteria provided P:2B:1O:1

Conservation

PhyloP100: 1.34

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ACTN3	NM_001104.4 linkuse as main transcript	c.1729C>T	p.Arg577Ter	stop_gained	15/21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3 linkuse as main transcript	c.1858C>T	p.Arg620Ter	stop_gained	15/21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2 linkuse as main transcript	c.1729C>T	p.Arg577Ter	stop_gained	15/21	1	NM_001104.4	ENSP00000426797	P1
ACTN3	ENST00000502692.5 linkuse as main transcript	c.1858C>T	p.Arg620Ter	stop_gained	15/21	2		ENSP00000422007

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

57028

AN:

151932

Hom.:

12131

Cov.:

show subpopulations

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.:

AF XY:

0.449

AC XY:

326110

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.156

Gnomad4 AMR exome

AF:

0.651

Gnomad4 ASJ exome

AF:

0.449

Gnomad4 EAS exome

AF:

0.486

Gnomad4 SAS exome

AF:

0.573

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.441

Gnomad4 OTH exome

AF:

0.442

GnomAD4 genome

AF:

0.375

AC:

57041

AN:

152054

Hom.:

12141

Cov.:

AF XY:

0.377

AC XY:

28028

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.546

Gnomad4 ASJ

AF:

0.455

Gnomad4 EAS

AF:

0.466

Gnomad4 SAS

AF:

0.583

Gnomad4 FIN

AF:

0.310

Gnomad4 NFE

AF:

0.442

Gnomad4 OTH

AF:

0.412

Alfa

AF:

0.431

Hom.:

29295

Bravo

AF:

0.382

ClinVar

Significance: Conflicting classifications of pathogenicity; Affects

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

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

INCREASED COLD TOLERANCE

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Sprinting performance

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

ACTININ, ALPHA-3 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Actn3 deficiency

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

Vest4

0.56

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over