11-66551332-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001104.4(ACTN3):c.241C>T(p.Leu81=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,608,516 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (59 hom.)
• Consequence: ACTN3 NM_001104.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.788

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 11-66551332-C-T is Benign according to our data. Variant chr11-66551332-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2641991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.788 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN3	NM_001104.4	c.241C>T	p.Leu81=	synonymous_variant	2/21	ENST00000513398.2
ACTN3	NM_001258371.3	c.370C>T	p.Leu124=	synonymous_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN3	ENST00000513398.2	c.241C>T	p.Leu81=	synonymous_variant	2/21	1	NM_001104.4	P1
ACTN3	ENST00000502692.5	c.370C>T	p.Leu124=	synonymous_variant	2/21	2
ACTN3	ENST00000511191.1	c.*208C>T		3_prime_UTR_variant, NMD_transcript_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.00607 AC: 924 AN: 152204 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00619 AC: 1488 AN: 240356 Hom.: 12 AF XY: 0.00623 AC XY: 808 AN XY: 129772

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00195

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00888

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00788 AC: 11479 AN: 1456194 Hom.: 59 Cov.: 31 AF XY: 0.00779 AC XY: 5635 AN XY: 723718

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00215

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00877

Gnomad4 OTH exome AF: 0.00801

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152322 Hom.: 9 Cov.: 32 AF XY: 0.00581 AC XY: 433 AN XY: 74484

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.00911

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00828 Hom.: 3

Bravo AF: 0.00555

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

ACTN3: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	7.5
Dann	Benign	0.71

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: rs187286120; hg19: chr11-66318803;