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.1 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.2 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.3 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.4 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.5 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).6
SLX4
Final classification
Likely Benign
SLX4 c.903G>C · p.Lys301Asn
SLX4
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.
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.
Classification rationale
PM2
BP1BP4
Likely Benign
SLX4 c.903G>C
PM2 + BP1 + BP4
→
Likely Benign
1
pvs1_gene_contextpvs1_variant_assessment
3
revelbayesdelspliceai ↗
4
pvs1_gene_context
6
generic_acmg_combination_rules
Gene diagram
· NM_032444.3 · variants mapped to exon structure
SLX4
NM_032444.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 18 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 1/31392 alleles (AF=0.0032%)no homozygotes
✓
BP1
supporting
Benign
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).
SLX4/FANCP: Fanconi anemia caused by biallelic loss-of-function variantsLoF mechanism supported per ClinGen SVI PVS1 gene-level eligibility assessmentZebrafish SLX4 knockout recapitulates Fanconi anemia phenotype (PMID:30540754)
✓
BP4
supporting
Benign
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: 0.148 (benignbelow 0.5 pathogenic threshold)BayesDel: -0.375 (benign
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No variant-specific functional evidence is available for NM_032444.3:c.903G>C (p.Lys301Asn).
PS4
No case-control or statistical enrichment data are available for this variant.
PM1
The variant does not lie in a statistically significant mutation hotspot per cancerhotspots.org.
PM6
No de novo data available for this variant.
PP1
No cosegregation data available.
PP2
HCI Prior data is not available for SLX4 (gene not supported).
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).
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).
PP5
The variant is absent from ClinVar and has not been classified as pathogenic by any reputable source.
Benign
BA1
Allele frequency in gnomAD (v2.1: 0.0032%; v4.1: 0.00006%) is far below the 1% BA1 threshold.
BS1
Allele frequency in gnomAD (v2.1: 0.0032%; v4.1: 0.00006%) is far below the 0.3% BS1 threshold.
BS2
No data are available on observation of this variant in healthy adults with full penetrance expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrating a neutral or non-deleterious effect have been identified for p.Lys301Asn.
BS4
No nonsegregation data or family studies available for this variant.
BP2
No data on observation in trans with a pathogenic variant in a recessive disorder.
BP5
No data available on observation of this variant in a case with an alternate molecular basis for disease.
BP6
The variant is absent from ClinVar and has not been classified as benign by any reputable source.
N/A · 4
PVS1 · PS1 · PM5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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).
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).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,028
0 hom
0 hom
European (non-Finnish) 1 / 1,180,036 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0032%
· 1 / 31,392
0 hom
0 hom
European (non-Finnish) 1 / 15,424 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107310564, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links