rs187286120

Variant names:

• chr11-66551332-C-T
• rs187286120
• NM_001104.4:c.241C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001104.4(ACTN3):​c.241C>T​(p.Leu81Leu) 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
• Publications: 4 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 -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 GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.241C>T	p.Leu81Leu	synonymous_variant	Exon 2 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.370C>T	p.Leu124Leu	synonymous_variant	Exon 2 of 21		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.241C>T	p.Leu81Leu	synonymous_variant	Exon 2 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.370C>T	p.Leu124Leu	synonymous_variant	Exon 2 of 21	2		ENSP00000422007.1
ACTN3	ENST00000511191.1	n.*208C>T		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000426236.1
ACTN3	ENST00000511191.1	n.*208C>T		3_prime_UTR_variant	Exon 2 of 5	5		ENSP00000426236.1

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

GnomAD2 exomes AF: 0.00619 AC: 1488 AN: 240356 AF XY: 0.00623

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 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

African (AFR) AF: 0.00144 AC: 48 AN: 33368

American (AMR) AF: 0.00153 AC: 67 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 430 AN: 25968

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39512

South Asian (SAS) AF: 0.00215 AC: 183 AN: 85108

European-Finnish (FIN) AF: 0.0102 AC: 539 AN: 53064

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00877 AC: 9727 AN: 1109352

Other (OTH) AF: 0.00801 AC: 482 AN: 60200

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

African (AFR) AF: 0.00156 AC: 65 AN: 41568

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00911 AC: 620 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

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

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.79

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

Other links and lift over

dbSNP: rs187286120; hg19: chr11-66318803;