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SLX4c.1732G>CUncertain significance
Print report
Variant interpretation report

SLX4 c.1732G>C, p.(Glu578Gln)

NM_032444.3:c.1732G>C NP_115820.2:p.(Glu578Gln) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SLX4

No gene-level summary was recorded for this case.

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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

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.

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 / 1,597,126 alleles

gnomAD v4.1: 1 / 1,597,126 alleles. Recorded AF 6.26125e-07. Recorded homozygote count 0.

gnomAD 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).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 23 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

ClinVar reports this variant as Uncertain significance (VCV001337411) based on a single clinical laboratory submission; no expert panel review or functional evidence is available.

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.

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1/217
  • 630 alleles (AF = 0.00046%)
  • gnomAD v4.1: 1/1
  • 597
  • 126 alleles (AF = 0.00006%)
  • No homozygotes observed
  • Highest subpopulation AF = 0.00105% (NFE v2.1)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.013 (strongly benign prediction)
  • BayesDel: -0.679 (benign prediction)
  • SpliceAI: max delta 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗

Not met · 23 · evaluated, threshold not reached

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). PVS1 is not applicable to missense variants under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
  • Missense variant p.Glu578Gln is not a predicted null variant
  • ClinGen SVI PVS1 framework (PMC6185798) restricts PVS1 to null variants
Sources
pvs1_generic_framework ↗pvs1_variant_assessmentpvs1_gene_context
PS1 No evidence that the same amino acid change (p.Glu578Gln) has been established as pathogenic in a previously classified variant. Details ▾Hide ▴
Still missing
  • No prior pathogenic classification for p.Glu578Gln or a nucleotide change producing the same amino acid substitution
PS2 No de novo occurrence data with confirmed paternity and maternity available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or family studies available
PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. The sole publication (PMID:25741868) is the ACMG/AMP guideline paper and does not mention this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence
Still missing
  • No in vitro or in vivo functional studies for p.Glu578Gln
Sources
oncokb ↗
PS4 No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals. ClinVar reports a single submitter classification of Uncertain significance with no phenotype-specific case series. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV001337411: single submitter
  • VUS
  • no case-control data
Still missing
  • No case-control or cohort enrichment data
Sources
clinvar ↗
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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue not statistically significant
  • No domain-level annotation placing codon 578 in a critical functional domain
Still missing
  • SLX4 domain architecture not annotated at residue-level in case materials
PM5 No pathogenic missense variant at the same codon (Glu578) with a different amino acid change was identified in ClinVar. Automated PM5 candidate harvesting returned no candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: no same-residue pathogenic comparators found at codon 578
Still missing
  • No same-codon pathogenic missense comparator available
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence data (without or with confirmed paternity) available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports in the literature
PP1 No co-segregation data in affected families is available for this variant. Details ▾Hide ▴
Still missing
  • No family studies or segregation analysis
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. Details ▾Hide ▴
Still missing
  • Missense constraint metrics not available for SLX4
PP3 Multiple in silico predictors suggest a benign effect: REVEL score = 0.013 (strongly benign), BayesDel score = -0.679 (benign). These do not support a deleterious effect; rather, they support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.013 (predicts benign)
  • BayesDel: -0.679 (predicts benign)
Sources
revelbayesdel
PP4 No patient phenotype or family history data specific to this variant is available. The ClinVar submission lists condition as 'not specified.' Details ▾Hide ▴
Evidence considered
  • ClinVar: condition 'not specified'
  • no phenotype data
Still missing
  • No phenotype information for the proband
Sources
clinvar ↗
PP5 ClinVar reports this variant as Uncertain significance (1 submitter, criteria provided, single submitter). The review status is not expert panel (0★–1★ equivalent), and the classification is not pathogenic. PP5 requires a pathogenic assertion from a reputable source; a VUS does not qualify. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV001337411: Uncertain significance
  • single submitter
Sources
clinvar ↗
BA1 gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.00046%
  • gnomAD v4.1 AF = 0.00006%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.00046%
  • gnomAD v4.1 AF = 0.00006%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data documenting observation of this variant in healthy adults for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available
BS3 No functional studies (in vitro or in vivo) demonstrating no deleterious effect for this variant. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific functional evidence
Still missing
  • No functional studies available for p.Glu578Gln
Sources
oncokb ↗
BS4 No non-segregation data in affected families is available. Details ▾Hide ▴
Still missing
  • No family segregation data
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. Missense variants have been reported in SLX4-associated disease contexts (e.g., endometrial and breast cancer cohorts per PMID:39400928). Details ▾Hide ▴
Evidence considered
  • SLX4 loss-of-function mechanism is supported for Fanconi anemia
  • Missense variants in SLX4 have been reported in disease contexts
Still missing
  • Mutational spectrum not fully characterized to confirm truncating-only disease mechanism
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic dominant allele or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
  • No phase information available
BP5 No observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data
BP6 ClinVar reports this variant as Uncertain significance, not benign. BP6 requires a reputable source to report the variant as benign; a VUS classification does not satisfy this criterion. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV001337411: Uncertain significance
Sources
clinvar ↗
PS5 No ClinVar-based PM5/PS5 same-codon pathogenic comparator variants were identified for codon 578. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no same-residue comparator variants
Still missing
  • No pathogenic variant at the same codon identified
Sources
pm5_candidates
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ANo second pathogenic variant in trans identified. PM3 requires biallelic observation for recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a substitution variant, not a protein-length-altering change (non-frameshift indel, stop-loss, initiation codon). PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion. BP3 applies to in-frame indels in repeat regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_032444.3:c.1732G>C is a missense variant (p.Glu578Gln), not a synonymous or intronic variant. BP7 only applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
SLX4
Transcript
NM_032444.3
Coding (HGVS c.)
NM_032444.3:c.1732G>C
Protein (HGVS p.)
NP_115820.2:p.(Glu578Gln)
GRCh38
chr16:3596345 C>G
GRCh37
chr16:3646346 C>G
ClinVar
1337411

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…
gnomAD v4.1 1 / 1,597,126 alleles AF 6.26e-07 · 0 homozygotes
gnomAD v2.1 1 / 217,630 alleles AF 4.59e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.3e-07 · 1 / 1,597,126 alleles · 0 hom
Remaining individuals1 / 61,752 1.6e-05
0 alternate alleles recorded in 9 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD v2.1

AF 4.6e-06 · 1 / 217,630 alleles · 0 hom
European (non-Finnish)1 / 95,426 1e-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= 6.26125e-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).

gnomAD 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).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -49 bp
0.030
SpliceAI acceptor gainat +146 bp
0.000
SpliceAI donor lossat -351 bp
0.000
SpliceAI donor gainat +392 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.013
BayesDel
-0.680

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.013 (strongly benign prediction)
  • BayesDel: -0.679 (benign prediction)
  • SpliceAI: max delta 0.03 (no splice impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors suggest a benign effect: REVEL score = 0.013 (strongly benign), BayesDel score = -0.679 (benign). These do not support a deleterious effect; rather, they support BP4. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.013 (predicts benign)
  • BayesDel: -0.679 (predicts benign)
Sources
revelbayesdel
BP7 N/ANM_032444.3:c.1732G>C is a missense variant (p.Glu578Gln), not a synonymous or intronic variant. BP7 only applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.013. BayesDel score = -0.679505.

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

  • 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. · 2015
    This is the ACMG/AMP standards and guidelines paper for sequence variant interpretation. NM_032444.3:c.1732G>C (p.Glu578Gln) is not mentioned. This paper was cited by the ClinVar submitter as a methodological reference for applying ACMG criteria to classify the variant.
    Does not name this variant
    PMID 25741868 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,597,126 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar 1 Uncertain significance 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

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= 6.26125e-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).

gnomAD 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).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.