The ACTN3 NM_001104.4:c.1729C>T (NP_001095.2:p.(Arg577Ter)) nonsense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Human muscle studies found complete absence of detectable alpha-actinin-3 protein in homozygous R577X individuals, but lacked documented clinical-laboratory assay validation for stronger strength. Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.ACTN3 encodes alpha-actinin-3, a skeletal-muscle structural protein that anchors and crosslinks actin filaments at the sarcomere’s Z lines. Common functional and non-functional forms are associated with differences in muscle performance, including athletic traits, but ACTN3 is not established as a cause of a specific disease and has no known established role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, supporting: human muscle studies found complete absence of detectable alpha-actinin-3 protein in homozygous R577X individuals, but lacked documented clinical-laboratory assay validation for stronger strength.
Met: gnomAD v4.1 grpmax FAF is 0.618616, exceeding the generic BA1 threshold of 0.05 in a population with 59,986 observed alleles.
Met: gnomAD v4.1 grpmax FAF is 0.618616, far above the generic BS1 threshold of 0.01 and supported by 59,986 observed alleles.
Benign: BA1 stand-alone benign is met by the high gnomAD frequency, with additional BS1 strong and PS3 supporting evidence applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 708,445 / 1,613,426 alleles. Recorded AF 0.439094. Recorded homozygote count 161361.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Benign. ClinVar API review status: criteria provided, single submitter.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The functional evidence supports PS3 at supporting strength because direct human muscle assays demonstrate loss of the ACTN3 gene product, while no stronger assay-validation calibration is documented.
BS3 is not met because the studies show absence of alpha-actinin-3 protein rather than preserved protein function or normal splicing.
Generic ACMG/AMP rules govern because no ACTN3 VCEP or CSPEC is available.
PS4 is not met because exact-variant case-control data show no enrichment and the computed OR is below 5.0 with a confidence interval including 1.0.
PP4 is not met because the variant is a common polymorphism without a highly specific single-gene disease phenotype.
PP5 and BP6 are not met because ClinVar contains no expert-panel classification eligible for these criteria.
BP5 is not assessed because the available co-occurrence report does not establish a citable alternate molecular basis for disease.
Population evidence strongly supports a benign common polymorphism: BA1 and BS1 are met using the gnomAD v4.1 filtering grpmax FAF, while PM2 is not met.
BS2 remains unassessed because the case does not define a fully penetrant early-onset ACTN3 disorder required by the criterion, although the numerous healthy homozygotes provide additional benign context.
No criteria match.
PS3 is met at supporting strength. Direct human skeletal-muscle studies show that the ACTN3 R577X allele corresponding to NM_001104.4:c.1729C>T, p.(Arg577Ter), produces complete absence of detectable alpha-actinin-3 protein in homozygous individuals, including immunocytochemistry and western-blot findings in muscle biopsies. The observation is biologically relevant to the encoded gene product and is supported by population-based protein studies, but the available evidence does not document a clinically validated, standardized diagnostic assay with explicit positive and negative assay controls or independent laboratory reproducibility sufficient for stronger calibration. The finding is therefore functional evidence of loss of gene product, not evidence of disease causality.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BA1 is met. In generic ACMG/AMP assessment, the default stand-alone threshold is allele frequency >=0.05 (ACMG/AMP 2015, PMID:25741868). gnomAD v4.1 reports 708445/1613426 alleles, AF=0.439094, with grpmax FAF=0.618616; the population supporting the grpmax FAF is large enough for the required >=2000 observed alleles (the Admixed American group has 59986 alleles). This is not an isolate-population popmax artifact. The exact variant is also documented as a common ACTN3 R577X polymorphism without an obvious neuromuscular phenotype (PMID:10192379), so the high frequency is concordant with benign interpretation rather than conflicting with a well-established pathogenic association.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is met. The generic SVI default threshold supplied for this case is >=0.01, and gnomAD v4.1 reports a filtering grpmax FAF of 0.618616, far above that threshold. The frequency is based on a sufficiently large population (Admixed American observed allele count 59986) and is not dependent on the small Amish, Ashkenazi Jewish, Middle Eastern, or remaining groups. ACTN3 R577X is a common polymorphism and published population studies report no obvious neuromuscular phenotype, so there is no disease prevalence, penetrance, or allelic-heterogeneity basis in the available evidence for withholding BS1 as a reduced-penetrance pathogenic allele.
Allele frequency is greater than expected for the disorder.
NM_001104.4:c.1729C>T is a confirmed nonsense variant, producing NP_001095.2:p.(Arg577Ter) in the MANE transcript and located in exon 15. The variant therefore has the consequence expected for a PVS1 candidate, but the required gene-level condition is not satisfied: ACTN3 loss of function is not established as a disease mechanism in the supplied evidence. The exact R577X allele is common in healthy populations, causes absence of alpha-actinin-3 without an obvious disease phenotype, and has been described as a non-pathogenic polymorphism. The predicted truncation is in the terminal coding exon and therefore is not sufficient by itself to establish pathogenic loss of function, while the high population frequency is inconsistent with a disease-causing null allele. PVS1 is consequently not met rather than downgraded to a lower strength.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
The governing ACMG/AMP rule requires a significantly increased prevalence in affected individuals, with OR or RR >5.0 and a confidence interval that excludes 1.0. The reviewed exact-variant literature does not show enrichment. In Japanese dystrophinopathy cases versus controls, the reported genotypes were 27/119 homozygous 577X cases versus 9/30 controls; using the reported genotype counts, the homozygote OR was 0.685 (95% CI 0.281-1.669), which does not meet OR >5.0 and whose CI includes 1.0. Using allele counts reconstructed from the reported genotypes (113/238 case alleles versus 34/60 control alleles), the allele OR was 0.691 (95% CI 0.391-1.223), likewise not enriched. Other studies report the common 577X allele in healthy controls and athlete cohorts, with no disease-specific case-control enrichment; PMID:17627799 found no significant genotype or allele-frequency differences in 457 triathletes versus 143 controls, and PMID:10192379 concluded that the stop codon is a non-pathogenic polymorphism. The literature_pass packet had no ai_classified_papers, so there were no classifier-read PS4 papers requiring additional verification; the available paper_extracts were checked against their extracted abstract/full-text findings.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is not met. The generic supporting threshold supplied for this case is <=0.0001, but gnomAD v4.1 shows the variant at AF=0.439094 (708445/1613426 alleles), with grpmax FAF=0.618616 and 161361 homozygotes. Therefore the variant is neither absent nor at an extremely low frequency in controls. gnomAD v2.1 absence does not override the substantially larger and current gnomAD v4.1 observation.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The governing rule requires a phenotype or family history highly specific for a disease with a single genetic etiology. The reviewed exact-variant studies describe ACTN3 R577X as a common polymorphism, alpha-actinin-3 deficiency without an abnormal muscular phenotype, athletic-performance traits, or lack of association with dystrophinopathy; they do not establish a highly specific phenotype or single-gene disease presentation for this case.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The governing rule concerns a reputable recent report of pathogenicity when the evidence is unavailable for independent evaluation. The exact-variant ClinVar record has no expert-panel submissions; its pathogenic assertions are OMIM submissions marked no assertion criteria provided, and the current ClinVar summary is a single-submitter Benign record. These ordinary/non-expert assertions cannot trigger PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. The directly relevant functional studies do not show an intact or unaffected ACTN3 gene product: they report complete absence of detectable alpha-actinin-3 protein in individuals homozygous for the R577X allele, corresponding to NM_001104.4:c.1729C>T, p.(Arg577Ter). Although the studies report no obvious muscular disease phenotype and suggest functional redundancy with alpha-actinin-2, absence of the ACTN3 protein is not evidence that the variant has no damaging effect on protein function; it is evidence of a null effect on the gene product. No validated assay demonstrating preserved protein function or normal splicing was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The governing rule concerns a reputable recent benign report when the evidence is unavailable for independent evaluation. ClinVar variation 18312 has no expert-panel submission; the benign record is a single-submitter laboratory assertion, while other benign OMIM submissions are marked no assertion criteria provided. Ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No clinical proband evidence establishes the disease phenotype, no parental genotypes or maternity/paternity confirmation are provided, and no family-history information is available. The reviewed ACTN3 p.(Arg577Ter) publications are population, phenotype-association, or protein studies rather than documented affected proband-parent trios; therefore de novo status cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM3 cannot be assessed because the available evidence does not identify a recessive ACTN3 disorder context, an affected proband carrying NM_001104.4:c.1729C>T, a pathogenic allele in the same individual, or parent/offspring testing establishing trans phase. The available ACTN3 publications describe common-population genotype frequencies and homozygous alpha-actinin-3 deficiency, not pathogenic-variant phase observations.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
No clinical proband evidence establishes the disease phenotype, and no parental genotypes or family-history information are provided. The reviewed ACTN3 p.(Arg577Ter) publications do not document an assumed de novo occurrence in a patient; consequently, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, variant-positive relatives, or genotype-phenotype co-segregation data are provided. The reviewed ACTN3 p.(Arg577Ter) publications report unrelated population cohorts rather than multiple affected family members; therefore PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
BS2 cannot be assessed definitively because no specific ACTN3 Mendelian disorder, inheritance model, or expectation of full penetrance by early adulthood is established in the case. The variant is observed homozygously in many population and healthy-control cohorts, including approximately 18% of healthy white individuals in Yang et al. 2003 and 80 homozygotes among 485 anonymous individuals in Mills et al. 2001; these observations strongly support benignity but do not satisfy the criterion's required disease-model condition without a defined disorder for which full early-age penetrance is expected.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members with documented genotypes are provided, so there is no evidence that the variant fails to segregate with disease. The reviewed ACTN3 p.(Arg577Ter) publications are unrelated-population or association studies and do not establish familial non-segregation; therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family.
BP2 cannot be assessed because no available case, family, or publication evidence documents NM_001104.4:c.1729C>T in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant. The available studies report genotype frequencies and alpha-actinin-3 deficiency, without cis/trans testing against a pathogenic variant.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. A separate case-report abstract in the broader case materials describes ACTN3 R577X co-occurring with SCN4A p.I1545V in a patient with acute rhabdomyolysis during transplantation, but the source is not represented by an exact PMID key in source_registry and the available text does not establish that the SCN4A finding is the alternate molecular basis responsible for the disease. The evidence is therefore insufficient for a defensible BP5 determination.
Variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_001104.4:c.1729C>T is a nonsense variant producing p.(Arg577Ter), an explicitly excluded truncating/protein-length-changing consequence. The generic PP3/BP4 scope limits these criteria to missense variants or splice-region/intronic variants assessed through the applicable predictor path; therefore the available SpliceAI max delta of 0.00 is not evaluated for PP3 and cannot support or negate it.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_001104.4:c.1729C>T is a nonsense variant producing p.(Arg577Ter), an explicitly excluded truncating/protein-length-changing consequence. A no-impact splice prediction cannot provide evidence of no impact on the gene product for a truncating variant, so the available SpliceAI max delta of 0.00 is not used for BP4.
BP4 on a frameshift or nonsense variant is not_applicable: a 'no predicted splice impact' result leaves the truncating protein effect in place, so it is not evidence of no impact on the gene product - a splice prediction for such a variant matters only to PVS1 (e.g. predicted rescue).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in ACTN3, mapped onto the exon structure of NM_001104.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American37426 / 59,986 | 0.6211996 hom |
| South Asian52207 / 91,078 | 0.5715132 hom |
| Amish513 / 906 | 0.57148 hom |
| East Asian21710 / 44,850 | 0.485370 hom |
| Middle Eastern2794 / 6,062 | 0.46661 hom |
| Ashkenazi Jewish13307 / 29,602 | 0.452998 hom |
| Remaining individuals27569 / 62,480 | 0.446181 hom |
| European (non-Finnish)520102 / 1,179,796 | 0.44114491 hom |
| European (Finnish)20505 / 63,700 | 0.323303 hom |
| African/African American12312 / 74,966 | 0.161081 hom |
This variant is present in gnomAD v4.1 (AF= 0.439094; MAF= 43.90936%, 708445/1613426 alleles, homozygotes = 161361) and has highest observed frequency in the Admixed American population (AF= 0.623912; MAF= 62.39122%, 37426/59986 alleles, homozygotes = 11996); grpmax FAF= 0.618616.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
PP3 is not applicable because NM_001104.4:c.1729C>T is a nonsense variant producing p.(Arg577Ter), an explicitly excluded truncating/protein-length-changing consequence. The generic PP3/BP4 scope limits these criteria to missense variants or splice-region/intronic variants assessed through the applicable predictor path; therefore the available SpliceAI max delta of 0.00 is not evaluated for PP3 and cannot support or negate it.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
BP4 is not applicable because NM_001104.4:c.1729C>T is a nonsense variant producing p.(Arg577Ter), an explicitly excluded truncating/protein-length-changing consequence. A no-impact splice prediction cannot provide evidence of no impact on the gene product for a truncating variant, so the available SpliceAI max delta of 0.00 is not used for BP4.
BP4 on a frameshift or nonsense variant is not_applicable: a 'no predicted splice impact' result leaves the truncating protein effect in place, so it is not evidence of no impact on the gene product - a splice prediction for such a variant matters only to PVS1 (e.g. predicted rescue).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001104.4:c.1729C>T in ACTN3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001095.2:p.(Arg577Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ACTN3, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. 2 cited in the classification.
The high allelic frequency of ACTN3 577X in the general population demonstrates that this stop codon is a non-pathogenic polymorphism in humans.
Location Results, paragraphs describing ACTN3 exon 16 R577X; Fig. 1 legend; Results, population-frequency analysis; Discussion
Context ACTN3 cDNA and genomic DNA sequencing; alpha-actinin-3 immunocytochemistry and western blotting in muscle biopsies; genotyping of 125 additional biopsies and 485 population DNA samples.
Absence of α-actinin-3 is not associated with an obvious disease phenotype, suggesting that ACTN3 is redundant in humans.
Location Introduction; Results, ‘There is marked population variation in the allelic frequency of 577R and 577X’; Discussion
Context ACTN3 exon 16 genotyping by PCR followed by DdeI restriction analysis in 485 anonymous human individuals (970 chromosomes) from multiple ethnic populations; additional genotyping of 36 baboons and 33 chimpanzees; human alpha-actinin-3 protein detection by western blot and skeletal-muscle expression studies.
We have recently demonstrated that the skeletal-muscle actin-binding protein a-actinin-3 is absent in 18% of healthy white individuals because of homozygosity for a common stop-codon polymorphism in the ACTN3 gene, R577X.
Abstract; Table 1; Results
These results indicate that the C1747T mutation of ACTN3 is highly observed among the Japanese and that the mutation is not a modifier of dystrophinopathy.
Results, concluding paragraph; Table I
We found that the 577XX genotype of the ACTN3 gene was less common among Finnish sprinters and that none of the top sprinters harboured this genotype.
Results, paragraph 3; Discussion, paragraph 2
Homozygosity for the nonsense mutation, 577X, within ACTN3 results in deficiency of alpha-actinin-3 but does not result in an abnormal muscular phenotype.
Introduction, paragraph 2; Methods, Subjects and DNA Extraction and Genotyping; Results, Genotype and Allele Distributions and Genotype Effects on Performance and Physiological Characteristics; Discussion and Conclusion
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.439094; MAF= 43.90936%, 708445/1613426 alleles, homozygotes = 161361) and has highest observed frequency in the Admixed American population (AF= 0.623912; MAF= 62.39122%, 37426/59986 alleles, homozygotes = 11996); grpmax FAF= 0.618616.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 18312)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.