11-66546762-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001258371.3(ACTN3):c.252C>T(p.Pro84=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,535,584 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (12 hom.)
• Consequence: ACTN3 NM_001258371.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.136

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-66546762-C-T is Benign according to our data. Variant chr11-66546762-C-T is described in ClinVar as [Benign]. Clinvar id is 3045587.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.136 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN3	NM_001258371.3	c.252C>T	p.Pro84=	synonymous_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN3	ENST00000502692.5	c.252C>T	p.Pro84=	synonymous_variant	1/21	2

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152076 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00179 AC: 241 AN: 134824 Hom.: 5 AF XY: 0.00234 AC XY: 172 AN XY: 73468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.000609 AC: 843 AN: 1383392 Hom.: 12 Cov.: 32 AF XY: 0.000897 AC XY: 612 AN XY: 682582

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.000605

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152192 Hom.: 1 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0115

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACTN3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.2
Dann	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs368835939; hg19: chr11-66314233;