About SLX4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SLX4 c.903G>C, p.(Lys301Asn)
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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/31,392 alleles, AF=3.19×10⁻⁵, 0.0032%) and gnomAD v4.1 (1/1,614,028 alleles, AF=6.20×10⁻⁷, 0.00006%), both well below the 0.1% PM2 threshold for non-VCEP contexts. No homozygotes observed. Absent from gnomAD-Canada.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
SLX4 is a Fanconi anemia gene (FANCP) where biallelic loss-of-function variants are the established disease mechanism for the canonical Fanconi anemia phenotype. In genes where primarily truncating variants cause disease, missense variants qualify for BP1 at supporting benign level. Literature review confirms SLX4 loss of function as a germline disease mechanism (PMID:30540754, PMID:28687356).
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence consistently suggest no impact on gene product. REVEL score 0.148 is well below the 0.5 pathogenic threshold, predicting a benign amino acid substitution. BayesDel score -0.375 (negative) supports a neutral effect. SpliceAI max delta 0.01 predicts no splicing alteration. All three independent in silico tools converge on a benign prediction.
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: PM2 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 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
1 / 1,614,028 alleles
gnomAD v4.1: 1 / 1,614,028 alleles. Recorded AF 6.19568e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18552e-05; MAF= 0.00319%, 1/31392 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SLX4, a protein involved in DNA damage repair, is mutated in the germline of the FANCP subtype of Fanconi anemia patients.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV107310564, n = 1 times).
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: 3 met · 9 not met · 10 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_032444.3:c.903G>C (p.Lys301Asn) is a missense variant in SLX4, a Fanconi anemia gene (FANCP) where biallelic loss-of-function variants are the established disease mechanism. As a missense change, PVS1 is not applicable.
The variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/31,392 alleles, AF 0.0032%) and gnomAD v4.1 (1/1,614,028 alleles, AF 0.00006%), meeting PM2 at supporting level for rarity below the 0.1% threshold.
Multiple in silico predictors consistently support a benign effect: REVEL 0.148 (benign), BayesDel -0.375 (neutral), and SpliceAI max delta 0.01 (no splicing impact), meeting BP4 at supporting benign level.
SLX4 is a gene where primarily truncating variants cause Fanconi anemia (FANCP); as a missense variant in a gene where the primary pathogenic mechanism is loss of function, BP1 applies at supporting benign level.
The variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. No variant-specific functional studies, case-control data, segregation data, or de novo observations are available.
The evidence is limited and conflicting: one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4). Under ACMG/AMP 2015 rules, the variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM2 SupportingThe variant is present at extremely low frequency in population databases: gnomAD v2.1 (1/31,392 alleles, AF=3.19×10⁻⁵, 0.0032%) and gnomAD v4.1 (1/1,614,028 alleles, AF=6.20×10⁻⁷, 0.00006%), both well below the 0.1% PM2 threshold for non-VCEP contexts. No homozygotes observed. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/31
- 392 alleles (AF=0.0032%)
- no homozygotes
- gnomAD v4.1: 1/1
- 614
- 028 alleles (AF=0.00006%)
- Absent from gnomAD-Canada v1.0
Sources
BP1 SupportingSLX4 is a Fanconi anemia gene (FANCP) where biallelic loss-of-function variants are the established disease mechanism for the canonical Fanconi anemia phenotype. In genes where primarily truncating variants cause disease, missense variants qualify for BP1 at supporting benign level. Literature review confirms SLX4 loss of function as a germline disease mechanism (PMID:30540754, PMID:28687356). Details ▾Hide ▴
Evidence considered
- SLX4/FANCP: Fanconi anemia caused by biallelic loss-of-function variants
- LoF mechanism supported per ClinGen SVI PVS1 gene-level eligibility assessment
- Zebrafish SLX4 knockout recapitulates Fanconi anemia phenotype (PMID:30540754)
Sources
pvs1_gene_context
BP4 SupportingMultiple lines of computational evidence consistently suggest no impact on gene product. REVEL score 0.148 is well below the 0.5 pathogenic threshold, predicting a benign amino acid substitution. BayesDel score -0.375 (negative) supports a neutral effect. SpliceAI max delta 0.01 predicts no splicing alteration. All three independent in silico tools converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.148 (benign
- below 0.5 pathogenic threshold)
- BayesDel: -0.375 (benign
- negative score indicates neutral)
- SpliceAI: max delta 0.01 (no predicted splicing impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No variant-specific functional evidence is available for NM_032444.3:c.903G>C (p.Lys301Asn). OncoKB reports 'Unknown Oncogenic Effect' with no curated functional studies for this variant. No published functional assays of this specific missense change were identified in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No in vitro or in vivo functional studies of p.Lys301Asn identified.
Sources
PM1 The variant does not lie in a statistically significant mutation hotspot per cancerhotspots.org. Residue-level functional domain constraint data is unavailable (HCI Prior not supported for SLX4). No evidence that p.Lys301 resides within a well-established critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot
- HCI Prior gene not supported.
Still missing
- No functional domain constraint data available for SLX4.
PP3 Multiple in silico predictors support a benign effect: REVEL score 0.148 (well below 0.5 pathogenic threshold), BayesDel score -0.375 (negative, indicating benign), and SpliceAI max delta 0.01 (no predicted splicing impact). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.148 (benign
- below 0.5 threshold)
- BayesDel: -0.375 (benign
- negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
PP5 The variant is absent from ClinVar and has not been classified as pathogenic by any reputable source. Although OncoKB provides gene-level context linking SLX4 to Fanconi anemia (FANCP), no variant-specific pathogenic assertion exists for NM_032444.3:c.903G>C. Details ▾Hide ▴
BA1 Allele frequency in gnomAD (v2.1: 0.0032%; v4.1: 0.00006%) is far below the 1% BA1 threshold. This variant is not a common population polymorphism. Details ▾Hide ▴
BS1 Allele frequency in gnomAD (v2.1: 0.0032%; v4.1: 0.00006%) is far below the 0.3% BS1 threshold. No subpopulation exceeds the threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF=0.0065% (NFE)
- v4.1 max subpop AF=0.000085% (NFE)
- all << 0.3%.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating a neutral or non-deleterious effect have been identified for p.Lys301Asn. OncoKB reports no variant-specific functional evidence, and no published functional characterization of this missense change was found in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional studies
- no published functional characterization identified.
Still missing
- No functional studies demonstrating no deleterious effect for p.Lys301Asn.
Sources
BP6 The variant is absent from ClinVar and has not been classified as benign by any reputable source. Details ▾Hide ▴
PS5 The variant is absent from ClinVar and has not been reported as pathogenic by any reputable source (clinical laboratory, expert panel, or curated database). The OncoKB gene-level annotation notes SLX4 involvement in Fanconi anemia but provides no variant-specific classification. Details ▾Hide ▴
Not assessed · 10 · no assessment recorded
PS2 No de novo data available for this variant. No family studies, parental testing, or confirmed de novo observations are present in the evidence record. Details ▾Hide ▴
Still missing
- No de novo testing or family studies available.
PS4 No case-control or statistical enrichment data are available for this variant. The variant is absent from ClinVar with no affected-vs-control comparison studies identified in the literature. Details ▾Hide ▴
Still missing
- No case-control or cohort enrichment data available.
PM6 No de novo data available for this variant. No confirmed de novo observations with maternity/paternity confirmation are present in the evidence record. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 No cosegregation data available. No family studies or linkage analysis have been performed for this variant. Details ▾Hide ▴
Still missing
- No cosegregation or family data available.
PP2 HCI Prior data is not available for SLX4 (gene not supported). Cannot compute missense Z-score or assess whether the gene has a low rate of benign missense variation. PP2 cannot be evaluated without gene-specific missense constraint metrics. Details ▾Hide ▴
Evidence considered
- HCI Prior: gene not supported
- no missense constraint data available.
Still missing
- No missense constraint metric (Z-score) available for SLX4.
PP4 No patient phenotype data or clinical information is available to assess whether the phenotype is highly specific for SLX4-related disease (Fanconi anemia or related cancer susceptibility). Details ▾Hide ▴
Still missing
- No patient phenotype information provided.
BS2 No data are available on observation of this variant in healthy adults with full penetrance expected at an early age. gnomAD provides population allele counts but no phenotype-linked carrier data to assess healthy adult observation. Details ▾Hide ▴
Still missing
- No phenotype-linked carrier data for healthy adult ascertainment.
BS4 No nonsegregation data or family studies available for this variant. Details ▾Hide ▴
Still missing
- No nonsegregation or family data available.
BP2 No data on observation in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Still missing
- No phase data or trans observation available.
BP5 No data available on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No data on cases with alternate molecular diagnosis.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_032444.3:c.903G>C is a missense variant (p.Lys301Asn) in exon 4 of SLX4. It does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework assessment is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo previously established pathogenic missense variant has been identified at residue p.Lys301. The variant is absent from ClinVar and no same-residue comparator was found. Without a known pathogenic comparator at this residue, PS1 cannot be assessed. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic comparator at p.Lys301 identified by PM5 candidate search.
Sources
clinvar ↗pm5_candidates
PM5 N/ANo same-residue comparator variants identified at p.Lys301. PM5 candidate search found zero eligible comparator variants, and the recommendation level is 'not_applicable'. Classic same-residue PM5 semantics cannot be confirmed. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparator variants identified at p.Lys301.
Sources
pm5_candidates
BP7 N/AThis variant is a missense change (c.903G>C, p.Lys301Asn), not a synonymous or non-coding variant. BP7 applies only to silent variants with no predicted splice impact and is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/intronic variants.
Identifiers
- Gene
- SLX4
- Transcript
- NM_032444.3
- Coding (HGVS c.)
- NM_032444.3:c.903G>C
- Protein (HGVS p.)
- NP_115820.2:p.(Lys301Asn)
- GRCh38
- chr16:3602165 C>G
- GRCh37
- chr16:3652166 C>G
- COSMIC
- COSV107310564
Gene diagram
Every interpreted variant in SLX4, mapped onto the exon structure of NM_032444.3. Select a row to find it on the plot.
SLX4NM_032444.3
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 SLX4
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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
1 / 1,614,028 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 31,392 alleles
AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,028 alleles · 0 hom
| European (non-Finnish)1 / 1,180,036 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,392 alleles · 0 hom
| European (non-Finnish)1 / 15,424 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-07; MAF= 0.00008%, 1/1180036 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18552e-05; MAF= 0.00319%, 1/31392 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.148
- BayesDel
- -0.375
How the predictions were used
BP4 SupportingMultiple lines of computational evidence consistently suggest no impact on gene product. REVEL score 0.148 is well below the 0.5 pathogenic threshold, predicting a benign amino acid substitution. BayesDel score -0.375 (negative) supports a neutral effect. SpliceAI max delta 0.01 predicts no splicing alteration. All three independent in silico tools converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.148 (benign
- below 0.5 pathogenic threshold)
- BayesDel: -0.375 (benign
- negative score indicates neutral)
- SpliceAI: max delta 0.01 (no predicted splicing impact)
Sources
PP3 Multiple in silico predictors support a benign effect: REVEL score 0.148 (well below 0.5 pathogenic threshold), BayesDel score -0.375 (negative, indicating benign), and SpliceAI max delta 0.01 (no predicted splicing impact). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.148 (benign
- below 0.5 threshold)
- BayesDel: -0.375 (benign
- negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
BP7 N/AThis variant is a missense change (c.903G>C, p.Lys301Asn), not a synonymous or non-coding variant. BP7 applies only to silent variants with no predicted splice impact and is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/intronic variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.148. BayesDel score = -0.374959.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,028 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_032444.3%3Ac.903G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-3652166-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-3602165-C-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-3602165-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_032444.3%3Ac.903G…
- OncoKB ↗www.oncokb.org/gene/SLX4/K301N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120651972
- 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= 6.19568e-07; MAF= 0.00006%, 1/1614028 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47432e-07; MAF= 0.00008%, 1/1180036 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18552e-05; MAF= 0.00319%, 1/31392 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.4834e-05; MAF= 0.00648%, 1/15424 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.148. BayesDel score = -0.374959.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SLX4, a protein involved in DNA damage repair, is mutated in the germline of the FANCP subtype of Fanconi anemia patients.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107310564, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.