LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-07
Case ID: NM_001104.4_c.1729C_T_20261107_181738
Framework: ACMG/AMP 2015
Variant classification summary

NM_001104.4:c.1729C>T

ACTN3  · NP_001095.2:p.(Arg577Ter)  · NM_001104.4
GRCh37: chr11:66328095 T>T  ·  GRCh38: chr11:66560624 C>T
Gene: ACTN3 Transcript: NM_001104.4
Final call
Benign
PS3 supporting BA1 stand-alone benign BS1 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
ACTN3
Transcript
NM_001104.4
Protein
NP_001095.2:p.(Arg577Ter)
gnomAD AF
0.43909358098853 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 supporting: human muscle studies found complete absence of detectable alpha-actinin-3 protein in homozygous R577X individuals.
2
BA1 stand-alone benign: gnomAD v4.1 filtering grpmax FAF is 0.618616, above the generic 0.05 threshold.
3
BS1 strong: gnomAD v4.1 filtering grpmax FAF is 0.618616, above the generic 0.01 threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone is sufficient for a Benign classification; BS1 strong and PS3 supporting are additional applied evidence.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Not met Not met: the common R577X null allele has 43.9% gnomAD v4.1 frequency and is reported without an overt muscle disease phenotype.
PMID:10192379 PMID:11440986 PMID:17627799 gnomad_v4
PS1 N/A Not applicable: PS1 requires a missense variant, and this is a nonsense variant.
generic_acmg_combination_rules
PS2 Not assessed Not assessed: no affected proband phenotype, parental genotypes, maternity/paternity confirmation, or family-history data are documented.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
PS3 Met 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.
PMID:10192379 PMID:11440986
PS4 Not met Not met: Japanese case-control data gave OR 0.685 (95% CI 0.281-1.669), far below the >5.0 threshold with a confidence interval including 1.0.
PMID:10797427 PMID:10192379 PMID:17627799 PMID:12879365 PMID:15886711 gnomad_v4
PM1 N/A Not applicable: PM1 requires a missense variant, and this is a nonsense variant.
generic_acmg_combination_rules
PM2 Not met Not met: gnomAD v4.1 reports AF 0.439094 and 161,361 homozygotes, far above the PM2 supporting threshold of 0.0001.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no affected-proband observation or parent/offspring testing establishes this variant in trans with a pathogenic allele.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a nonsense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 N/A Not applicable: PM5 requires a missense variant, and this is a nonsense variant.
generic_acmg_combination_rules
PM6 Not assessed Not assessed: no affected patient with an assumed de novo variant and unconfirmed parental testing is documented.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
PP1 Not assessed Not assessed: no multiple affected relatives, informative meioses, or genotype-phenotype co-segregation data are documented.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
PP2 N/A Not applicable: PP2 requires a missense variant, and this is a nonsense variant.
generic_acmg_combination_rules
PP3 N/A Not applicable: the nonsense change p.(Arg577Ter) is outside PP3's missense or splice-region/intronic scope, regardless of SpliceAI max delta 0.00.
PP4 Not met Not met: reviewed studies describe a common ACTN3 polymorphism without a highly specific single-gene disease phenotype.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:17627799
PP5 Not met Not met: ClinVar shows zero expert-panel submissions, and the pathogenic assertions are non-expert submissions without assertion criteria.
clinvar
BA1 Met 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.
gnomad_v4 PMID:10192379
BS1 Met 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.
gnomad_v4 PMID:10192379 PMID:11440986
BS2 Not assessed Not assessed: healthy homozygotes are common, including approximately 18% of healthy white individuals, but no fully penetrant early-onset ACTN3 disorder is defined.
PMID:12879365 PMID:11440986 PMID:17627799
BS3 Not met Not met: homozygous R577X individuals lacked detectable alpha-actinin-3 protein, so the studies do not show no damaging effect on protein function or splicing.
PMID:10192379 PMID:11440986
BS4 Not assessed Not assessed: no affected relatives with documented genotypes are available to demonstrate lack of segregation.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
BP1 N/A Not applicable: BP1 requires a missense variant, and this is a nonsense variant.
generic_acmg_combination_rules
BP2 Not assessed Not assessed: no family or case data establish the variant in trans or cis with a pathogenic variant under the BP2 definition.
PMID:10192379 PMID:10797427 PMID:11440986 PMID:12879365 PMID:15886711 PMID:17627799
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a nonsense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 N/A Not applicable: BP4 excludes nonsense variants, so SpliceAI max delta 0.00 cannot counter the truncating p.(Arg577Ter) consequence.
BP5 Not assessed Not assessed: ACTN3 R577X co-occurred with SCN4A p.I1545V, but an established alternate molecular basis is not documented in a citable registry source.
BP6 Not met Not met: the ClinVar benign record is a single-submitter assertion with zero expert-panel submissions, not an eligible expert-panel benign classification.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a nonsense variant.
generic_acmg_combination_rules
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