LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-16
Case ID: NM_003579.4_c.888C_T_20260716_023649
Framework: ACMG/AMP 2015
Variant classification summary

NM_003579.4:c.888C>T

RAD54L  · NP_003570.2:p.(Asp296=)  · NM_003579.4
GRCh37: chr1:46727054 C>T  ·  GRCh38: chr1:46261382 C>T
Gene: RAD54L Transcript: NM_003579.4
Final call
Likely Benign
BP6 supporting benign BP7 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
RAD54L
Transcript
NM_003579.4
Protein
NP_003570.2:p.(Asp296=)
gnomAD AF
0.00040586980688032975 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_003579.4(RAD54L):c.888C>T (p.Asp296=) is a synonymous variant with no predicted impact on splicing (SpliceAI max delta 0.02), meeting BP7 at supporting strength.
2
This variant has been reported in ClinVar as Likely benign by two clinical laboratories (ClinVarID 801488), meeting BP6 at supporting strength.
3
REVEL, BayesDel, and HCI prior scores are not available for this variant. SpliceAI alone does not constitute multiple lines of computational evidence required for BP4.
4
The variant is present in gnomAD v2.1 (103/282,688 alleles, AF=0.036%) and gnomAD v4.1 (655/1,613,818 alleles, AF=0.041%). The allele frequency is below the BS1 threshold (0.3%) and far below the BA1 threshold (5%). The variant is observed across multiple populations, which is inconsistent with PM2 absence.
5
No functional studies, de novo observations, co-segregation data, case-control data, or phenotype information are available for this variant. All other assessed criteria are not met or not applicable.
6
No CSPEC or VCEP framework exists for RAD54L. The generic ACMG/AMP 2015 classification framework (PMID:25741868) was applied.
7
Two supporting benign criteria (BP6, BP7) are met. Per the generic ACMG/AMP combination rules, two supporting benign criteria classify a variant as Likely Benign.
Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.
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 N/A This is a synonymous variant (p.Asp296=) that does not fall into any PVS1 null-variant category (nonsense, frameshift, canonical ±1,2 splice, initiation codon, or exon deletion). Not eligible for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798).
pvs1_generic_framework pvs1_variant_assessment
PS1 N/A This variant is synonymous (p.Asp296=) and produces no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant arising from a different nucleotide change, which is not applicable for silent variants.
PS2 Not met No de novo observation reported for this variant in ClinVar, literature, or any reviewed source.
PS3 Not met No functional studies testing this exact variant or a systematically characterized range that includes c.888 were identified. The only literature source (PMID:25741868) is the ACMG/AMP guidelines paper and contains no functional data.
PS4 Not met No case-control or prevalence data comparing this variant in affected versus unaffected individuals is available.
PS5 Not met ClinVar classifies this variant as Likely benign (ClinVarID 801488), not pathogenic. PS5 requires a reputable source to report the variant as pathogenic.
clinvar
PM1 Not met No statistically significant mutational hotspot at this residue was identified (cancerhotspots.org). No domain-level evidence in the case materials specifically characterizes codon 296 as critical. The RAD54L SNI2/RecA-like helicase domain spans residues ~200-600, but no functional domain characterization with variant-specific resolution for position 296 is available in the current evidence.
PM2 Not met This variant is present in gnomAD v2.1 (103/282,688 alleles, AF=0.036%) and gnomAD v4.1 (655/1,613,818 alleles, AF=0.041%), including 0 homozygotes. While the allele frequency is below 0.1%, the variant is observed across multiple populations in several hundred individuals and is not absent from population databases. Additionally, this is a synonymous variant with no predicted functional consequence, limiting the rationale for applying PM2.
gnomad_v2 gnomad_v4
PM5 N/A This variant is synonymous (p.Asp296=), not a missense change. PM5 requires a novel missense change at the same amino acid residue as a known pathogenic missense variant.
pm5_candidates
PM6 Not met No de novo observation with or without confirmed parentage is reported for this variant.
PP1 Not met No co-segregation data with disease in multiple affected family members is available for this variant.
PP2 N/A This is a synonymous variant, not a missense change. PP2 is specifically applicable to missense variants in genes with a low rate of benign missense variation.
PP3 Not met No in silico tools predict a deleterious effect. REVEL and BayesDel scores are unavailable for this variant. SpliceAI predicts no splicing impact (max delta score 0.02). HCI prior is not available for RAD54L.
spliceai
PP4 Not met No patient phenotype or family history data specific to the disease gene is available for adjudication.
PP5 Not met ClinVar classifies this variant as Likely benign, not pathogenic. Additionally, the review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold for mandatory PP5 application.
clinvar
BA1 Not met The highest observed allele frequency is 0.065% (gnomAD v2.1 European non-Finnish) and 0.099% (gnomAD v4.1 Middle Eastern), both far below the 5% threshold for BA1.
gnomad_v2 gnomad_v4
BS1 Not met The global allele frequency is 0.036% (gnomAD v2.1) and 0.041% (gnomAD v4.1), below the 0.3% BS1 threshold for a non-VCEP assessment.
gnomad_v2 gnomad_v4
BS2 Not met No data on observation of this variant in a healthy adult individual for a fully penetrant disorder is available.
BS3 Not met No experimental functional studies demonstrating a benign effect for this variant were identified. SpliceAI prediction (max delta 0.02) is in silico evidence, not experimental functional data suitable for BS3.
BS4 Not met No evidence of lack of segregation with disease in affected family members is available.
BP1 N/A This is a synonymous variant, not a truncating variant. Additionally, loss of function is a supported disease mechanism for RAD54L based on germline literature review.
pvs1_gene_context
BP2 Not met No evidence that this variant has been observed in trans with a pathogenic variant in RAD54L.
BP4 Not met BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI is available (max delta 0.02), and REVEL/BayesDel/HCI prior scores are not available. A single line of in silico evidence is insufficient to meet BP4.
spliceai
BP5 Not met No evidence that this variant has been observed in a case with an alternate molecular basis for disease.
BP6 Met This variant is classified as Likely benign in ClinVar (ClinVarID 801488) by 2 clinical laboratories (Mendelics, Ambry Genetics). ClinVar is a reputable source for variant classification.
clinvar
BP7 Met This is a synonymous variant (NM_003579.4:c.888C>T, p.Asp296=) with no predicted impact on splicing. SpliceAI predicts a maximum delta score of 0.02, indicating no significant alteration to splice consensus sequences or creation of new splice sites. The variant is present in gnomAD across multiple populations, inconsistent with high nucleotide conservation.
spliceai gnomad_v2 gnomad_v4
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