NM_032444.3:c.1732G>C (p.Glu578Gln) is a missense variant in SLX4, a Fanconi anemia pathway gene (FANCP) with an established loss-of-function disease mechanism.1 This variant is extremely rare in population databases, observed in 1/217,630 alleles in gnomAD v2.1 (AF = 0.00046%) and 1/1,597,126 alleles in gnomAD v4.1 (AF = 0.00006%), with no homozygotes, satisfying PM2 at supporting strength.2 Multiple in silico predictors indicate a benign effect: REVEL score 0.013, BayesDel score -0.679, and SpliceAI max delta 0.03, satisfying BP4 at supporting benign strength.3 ClinVar reports this variant as Uncertain significance (VCV001337411) based on a single clinical laboratory submission; no expert panel review or functional evidence is available.4 No variant-specific functional studies, segregation data, de novo reports, or case-control analyses were identified. The sole cited publication (PMID:25741868) is the ACMG/AMP guideline paper and does not mention this variant.5 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced at Uncertain significance under generic ACMG/AMP 2015 combination rules.6
SLX4
Final classification
VUS
SLX4 c.1732G>C · p.Glu578Gln
SLX4
NM_032444.3:c.1732G>C (p.Glu578Gln) is a missense variant in SLX4, a Fanconi anemia pathway gene (FANCP) with an established loss-of-function disease mechanism.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
SLX4 c.1732G>C
PM2 + BP4
→
VUS
Gene diagram
· NM_032444.3 · variants mapped to exon structure
SLX4
NM_032444.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 22 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases: gnomAD v2.1 AF = 4.59e-6 (1/217,630 alleles), v4.1 AF = 6.26e-7 (1/1,597,126 alleles), well below the 0.1% threshold for PM2. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: 1/217630 alleles (AF = 0.00046%)gnomAD v4.1: 1/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score = 0.013 (strongly predicts benign), BayesDel score = -0.679 (predicts benign), and SpliceAI max delta = 0.03 (no predicted splice impact).
REVEL: 0.013 (strongly benign prediction)BayesDel: -0.679 (benign prediction)SpliceAI: max delta 0.03 (no splice impact)
Assessed · not applied
Pathogenic
PVS1
NM_032444.3:c.1732G>C is a missense variant (p.Glu578Gln) and does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus).
PS1
No evidence that the same amino acid change (p.Glu578Gln) has been established as pathogenic in a previously classified variant.
PS2
No de novo occurrence data with confirmed paternity and maternity available for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals.
PM1
This variant does not lie in a statistically significant hotspot (cancerhotspots.org) and no curated functional domain evidence specific to residue 578 was identified in the case materials.
PM5
No pathogenic missense variant at the same codon (Glu578) with a different amino acid change was identified in ClinVar.
PM6
No de novo occurrence data (without or with confirmed paternity) available for this variant.
PP1
No co-segregation data in affected families is available for this variant.
PP2
No gene-level missense constraint data (e.g., Z-score, gnomAD missense OE ratio) was available in the case materials to assess whether SLX4 has a low rate of benign missense variation.
PP3
Multiple in silico predictors suggest a benign effect: REVEL score = 0.013 (strongly benign), BayesDel score = -0.679 (benign).
PP4
No patient phenotype or family history data specific to this variant is available.
PP5
ClinVar reports this variant as Uncertain significance (1 submitter, criteria provided, single submitter).
Benign
BA1
gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 1% BA1 threshold.
BS1
gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 0.3% BS1 threshold.
BS2
No data documenting observation of this variant in healthy adults for a disorder with full penetrance expected at an early age.
BS3
No functional studies (in vitro or in vivo) demonstrating no deleterious effect for this variant.
BS4
No non-segregation data in affected families is available.
BP1
Although SLX4 loss-of-function is a supported disease mechanism (Fanconi anemia FANCP subtype), there is insufficient evidence that only truncating variants cause disease in SLX4.
BP2
No observation of this variant in trans with a pathogenic dominant allele or in cis with a pathogenic variant.
BP5
No observation of this variant in a case with an alternate molecular basis for disease.
BP6
ClinVar reports this variant as Uncertain significance, not benign.
N/A · 4
PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.26125e-07; MAF= 0.00006%, 1/1597126 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61938e-05; MAF= 0.00162%, 1/61752 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 4.59495e-06; MAF= 0.00046%, 1/217630 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.04793e-05; MAF= 0.00105%, 1/95426 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,597,126
0 hom
0 hom
Remaining individuals 1 / 61,752 |
0.0016% |
+ 9 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.00046%
· 1 / 217,630
0 hom
0 hom
European (non-Finnish) 1 / 95,426 |
0.001% |
+ 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1337411)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.013. BayesDel score = -0.679505.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
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.
CLINVAR