11-66546753-C-G

Variant names:

• chr11-66546753-C-G
• rs150880895
• NM_001258371.3:c.243C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001258371.3(ACTN3):​c.243C>G​(p.Pro81Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,535,636 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (20 hom.)
• Consequence: ACTN3 NM_001258371.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.282
• Publications: 1 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-66546753-C-G is Benign according to our data. Variant chr11-66546753-C-G is described in ClinVar as [Benign]. Clinvar id is 3050805.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.282 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00876 (1334/152208) while in subpopulation AFR AF = 0.0299 (1242/41522). AF 95% confidence interval is 0.0285. There are 21 homozygotes in GnomAd4. There are 596 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001258371.3	c.243C>G	p.Pro81Pro	synonymous_variant	Exon 1 of 21		NP_001245300.2
ACTN3	NM_001104.4	c.-185C>G		upstream_gene_variant		ENST00000513398.2	NP_001095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000502692.5	c.243C>G	p.Pro81Pro	synonymous_variant	Exon 1 of 21	2		ENSP00000422007.1
ACTN3	ENST00000513398.2	c.-185C>G		upstream_gene_variant		1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.-185C>G		upstream_gene_variant		5		ENSP00000426236.1

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1331 AN: 152090 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00206 AC: 277 AN: 134650 AF XY: 0.00132

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.000483

GnomAD4 exome AF: 0.000921 AC: 1274 AN: 1383428 Hom.: 20 Cov.: 32 AF XY: 0.000769 AC XY: 525 AN XY: 682602

African (AFR) AF: 0.0317 AC: 1001 AN: 31578

American (AMR) AF: 0.00244 AC: 87 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000757 AC: 6 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33870

Middle Eastern (MID) AF: 0.00129 AC: 7 AN: 5420

European-Non Finnish (NFE) AF: 0.0000491 AC: 53 AN: 1078890

Other (OTH) AF: 0.00207 AC: 120 AN: 57844

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152208 Hom.: 21 Cov.: 32 AF XY: 0.00801 AC XY: 596 AN XY: 74416

African (AFR) AF: 0.0299 AC: 1242 AN: 41522

American (AMR) AF: 0.00432 AC: 66 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68002

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00569 Hom.: 3

Bravo AF: 0.0111

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ACTN3-related disorder Benign:1

Mar 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.78
CADD	Benign	3.2
DANN	Benign	0.50
PhyloP100		-0.28
PromoterAI		0.095	Neutral

Splicing

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

Other links and lift over

dbSNP: rs150880895; hg19: chr11-66314224;