NM_032444.3:c.903G>C

SLX4 · NP_115820.2:p.(Lys301Asn) · NM_032444.3

GRCh37: chr16:3652166 C>G · GRCh38: chr16:3602165 C>G

Gene: SLX4 Transcript: NM_032444.3

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

SLX4

Transcript

NM_032444.3

Protein

NP_115820.2:p.(Lys301Asn)

gnomAD AF

6.195679381026847e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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	NM_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.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.	clinvar pm5_candidates
PS2	Not assessed	No de novo data available for this variant. No family studies, parental testing, or confirmed de novo observations are present in the evidence record.
PS3	Not met	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.	oncokb
PS4	Not assessed	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.
PS5	Not met	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.	clinvar oncokb
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant. No confirmed de novo observations with maternity/paternity confirmation are present in the evidence record.
PP1	Not assessed	No cosegregation data available. No family studies or linkage analysis have been performed for this variant.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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).
PP5	Not met	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.	clinvar oncokb
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not met	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.	oncokb
BS4	Not assessed	No nonsegregation data or family studies available for this variant.
BP1	Met	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).	pvs1_gene_context
BP2	Not assessed	No data on observation in trans with a pathogenic variant in a recessive disorder.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not assessed	No data available on observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not met	The variant is absent from ClinVar and has not been classified as benign by any reputable source.	clinvar
BP7	N/A	This 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.

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