NM_001104.4:c.249G>A

Variant names:

• chr11-66551340-G-A
• rs192076014
• NM_001104.4:c.249G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001104.4(ACTN3):​c.249G>A​(p.Leu83Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,606,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: ACTN3 NM_001104.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 11-66551340-G-A is Benign according to our data. Variant chr11-66551340-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2641992.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.91 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.249G>A	p.Leu83Leu	synonymous_variant	Exon 2 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.378G>A	p.Leu126Leu	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.249G>A	p.Leu83Leu	synonymous_variant	Exon 2 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000502692.5	c.378G>A	p.Leu126Leu	synonymous_variant	Exon 2 of 21	2		ENSP00000422007.1
ACTN3	ENST00000511191.1	n.*216G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000426236.1
ACTN3	ENST00000511191.1	n.*216G>A		3_prime_UTR_variant	Exon 2 of 5	5		ENSP00000426236.1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000160 AC: 38 AN: 237084 AF XY: 0.0000938

Gnomad AFR exome AF: 0.00238

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.0000660 AC: 96 AN: 1454360 Hom.: 0 Cov.: 31 AF XY: 0.0000609 AC XY: 44 AN XY: 722666

African (AFR) AF: 0.00222 AC: 74 AN: 33312

American (AMR) AF: 0.0000920 AC: 4 AN: 43470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 84836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52940

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108530

Other (OTH) AF: 0.000233 AC: 14 AN: 60162

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74504

African (AFR) AF: 0.00224 AC: 93 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000906 Hom.: 0

Bravo AF: 0.000767

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTN3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.3
DANN	Benign	0.73
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192076014; hg19: chr11-66318811;