About RAD54L
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD54L c.888C>T, p.(Asp296=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP6Supporting
BP6 · supporting
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.
BP7Supporting
BP7 · supporting
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.
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP6 supporting benign, BP7 supporting benign; combination = 2 supporting benign, which maps to Likely Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
655 / 1,613,818 alleles
gnomAD v4.1: 655 / 1,613,818 alleles. Recorded AF 0.00040587. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000364359; MAF= 0.03644%, 103/282688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00065081; MAF= 0.06508%, 84/129070 alleles, homozygotes = 0); grpmax FAF= 0.00053859.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 19 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant has been reported in ClinVar as Likely benign by two clinical laboratories (ClinVarID 801488), meeting BP6 at supporting strength.
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.
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.
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.
No CSPEC or VCEP framework exists for RAD54L. The generic ACMG/AMP 2015 classification framework (PMID:25741868) was applied.
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.
No criteria match.
Met · 2
BP6 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- ClinVar Likely benign from 2 clinical laboratories (ClinVarID 801488)
Sources
BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.(Asp296=)
- SpliceAI max delta 0.02 (no splicing impact)
- observed in gnomAD across populations
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo observation reported for this variant in ClinVar, literature, or any reviewed source. Details ▾Hide ▴
Still missing
- No de novo data available
PS3 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. Details ▾Hide ▴
Still missing
- No functional data for this variant or a systematically characterized range that includes it
PS4 No case-control or prevalence data comparing this variant in affected versus unaffected individuals is available. Details ▾Hide ▴
Still missing
- No case-control or enrichment data available
PM1 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. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot
- no residue-specific domain evidence for position 296
Still missing
- Protein domain mapping at codon 296 not available in current evidence
PM2 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. Details ▾Hide ▴
Evidence considered
- Present in gnomAD v2.1 (AF=0.036%) and v4.1 (AF=0.041%)
- not absent from population databases
Sources
PM6 No de novo observation with or without confirmed parentage is reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data available
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 (no splicing impact)
- REVEL/BayesDel/HCI not available
Still missing
- REVEL and BayesDel scores not available
- HCI prior not supported for RAD54L
Sources
PP4 No patient phenotype or family history data specific to the disease gene is available for adjudication. Details ▾Hide ▴
Still missing
- No phenotype data available
PP5 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. Details ▾Hide ▴
BA1 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. Details ▾Hide ▴
Evidence considered
- Maximum AF = 0.099% (gnomAD v4.1 Middle Eastern)
- well below 5% threshold
Sources
BS1 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. Details ▾Hide ▴
BS2 No data on observation of this variant in a healthy adult individual for a fully penetrant disorder is available. Details ▾Hide ▴
Still missing
- No healthy adult observation data for fully penetrant disorder
BS3 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. Details ▾Hide ▴
Still missing
- No experimental functional studies for this variant
BS4 No evidence of lack of segregation with disease in affected family members is available. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No evidence that this variant has been observed in trans with a pathogenic variant in RAD54L. Details ▾Hide ▴
Still missing
- No trans observation data available
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02
- only one line of computational evidence
- insufficient for BP4
Still missing
- REVEL
- BayesDel
- and HCI prior scores not available
- lack of multiple in silico lines
Sources
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
PS5 ClinVar classifies this variant as Likely benign (ClinVarID 801488), not pathogenic. PS5 requires a reputable source to report the variant as pathogenic. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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). Details ▾Hide ▴
Evidence considered
- Synonymous variant p.(Asp296=)
- variant bucket 'other' per PVS1 scaffold
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no amino acid change to compare
PM5 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- no missense residue context available
Sources
pm5_candidates
PP2 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- PP2 is defined for missense variants
BP1 N/AThis is a synonymous variant, not a truncating variant. Additionally, loss of function is a supported disease mechanism for RAD54L based on germline literature review. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- LOF mechanism supported for RAD54L
Sources
pvs1_gene_context
Identifiers
- Gene
- RAD54L
- Transcript
- NM_003579.4
- Coding (HGVS c.)
- NM_003579.4:c.888C>T
- Protein (HGVS p.)
- NP_003570.2:p.(Asp296=)
- GRCh38
- chr1:46261382 C>T
- GRCh37
- chr1:46727054 C>T
- ClinVar
- 801488
Gene diagram
Every interpreted variant in RAD54L, mapped onto the exon structure of NM_003579.4. Select a row to find it on the plot.
RAD54LNM_003579.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RAD54L
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
655 / 1,613,818 alleles
AF 0.000406 · 0 homozygotes · FAF 0.000472
gnomAD v2.1
103 / 282,688 alleles
AF 0.000364 · 0 homozygotes · FAF 0.000539
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00041 · 655 / 1,613,818 alleles · 0 hom · FAF 0.00047
| Middle Eastern6 / 6,062 | 0.00099 |
| European (non-Finnish)597 / 1,179,946 | 0.00051 |
| Remaining individuals20 / 62,498 | 0.00032 |
| Admixed American13 / 59,988 | 0.00022 |
| South Asian11 / 91,028 | 0.00012 |
| African/African American6 / 74,926 | 8e-05 |
| Ashkenazi Jewish1 / 29,608 | 3.4e-05 |
| European (Finnish)1 / 63,992 | 1.6e-05 |
0 alternate alleles recorded in 2 other groups: Amish, East Asian.
gnomAD v2.1
AF 0.00036 · 103 / 282,688 alleles · 0 hom · FAF 0.00054
| European (non-Finnish)84 / 129,070 | 0.00065 |
| Remaining individuals3 / 7,218 | 0.00042 |
| Admixed American7 / 35,428 | 0.0002 |
| South Asian5 / 30,610 | 0.00016 |
| African/African American4 / 24,942 | 0.00016 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00040587; MAF= 0.04059%, 655/1613818 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000989772; MAF= 0.09898%, 6/6062 alleles, homozygotes = 0); grpmax FAF= 0.00047202.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000364359; MAF= 0.03644%, 103/282688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00065081; MAF= 0.06508%, 84/129070 alleles, homozygotes = 0); grpmax FAF= 0.00053859.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- Synonymous variant p.(Asp296=)
- SpliceAI max delta 0.02 (no splicing impact)
- observed in gnomAD across populations
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02 (no splicing impact)
- REVEL/BayesDel/HCI not available
Still missing
- REVEL and BayesDel scores not available
- HCI prior not supported for RAD54L
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02
- only one line of computational evidence
- insufficient for BP4
Still missing
- REVEL
- BayesDel
- and HCI prior scores not available
- lack of multiple in silico lines
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015The 2015 ACMG/AMP standards and guidelines for the interpretation of sequence variants. This paper provides the generic classification framework and combination rules applied in this assessment. NM_003579.4:c.888C>T (RAD54L) is not mentioned.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
655 / 1,613,818 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
2 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/801488/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-46727054-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-46261382-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-46261382-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003579.4%3Ac.888C…
- OncoKB ↗www.oncokb.org/gene/RAD54L/D296=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD54L+c.888C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00040587; MAF= 0.04059%, 655/1613818 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000989772; MAF= 0.09898%, 6/6062 alleles, homozygotes = 0); grpmax FAF= 0.00047202.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000364359; MAF= 0.03644%, 103/282688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00065081; MAF= 0.06508%, 84/129070 alleles, homozygotes = 0); grpmax FAF= 0.00053859.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 801488)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.