SLX4c.5242C>TUncertain significance

Print report

Variant interpretation report

SLX4 c.5242C>T, p.(Gln1748Ter)

NM_032444.3:c.5242C>T NP_115820.2:p.(Gln1748Ter) 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.

Key facts

Evidence used: 2 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Uncertain significance
Pipeline record: 23 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (moderate): NM_032444.3:c.5242C>T is a nonsense variant predicted to produce a truncated protein at p.Gln1748Ter (Q1748*). SLX4 loss of function is an established disease mechanism for Fanconi anemia subtype FA-P, and the gene passes the PVS1 gene-level gate. However, the variant is located in the terminal exon (exon 15 of 15), predicting escape from nonsense-mediated decay and production of a protein truncated by only 87 C-terminal amino acids (4.7% of the 1835-residue protein). The truncation removes the C-terminal ~50% of the SLX1-binding domain (SBD, residues 1632–1834), a functionally critical region required for SLX1 interaction and Holliday junction resolvase activity. Under PMC6185798 guidance for last-exon nonsense variants that escape NMD but disrupt a critical functional domain, PVS1 is applied at moderate strength.
PM1 (moderate): The variant p.Gln1748Ter is located within the SLX1-binding domain (SBD) of SLX4, a well-characterized critical functional domain spanning residues 1632–1834. The SBD is the extreme C-terminal conserved domain (CCD) that is both necessary and sufficient for SLX1 interaction, and SLX1 binding is required for Holliday junction resolvase activity. Domain mapping was established by systematic co-immunoprecipitation truncation analysis in PMID:19596235 (Fekairi et al. 2009, Figure 2A,C) and PMID:19596236 (Svendsen et al. 2009, Figure 2B, 4E). The nonsense variant truncates the protein within this domain, removing the C-terminal 87 amino acids and disrupting the conserved SBD. No benign missense variation has been observed in this domain in population databases at appreciable frequency. PM1 is met at moderate strength based on location in an experimentally defined, functionally critical protein domain whose disruption is consistent with the established loss-of-function disease mechanism.
PM2 (supporting): NM_032444.3:c.5242C>T is absent from or observed at extremely low frequency in large population databases. In gnomAD v2.1, the allele frequency is 3.20 × 10⁻⁵ (0.0032%, 9/281,628 alleles, 0 homozygotes) with grpmax filtering AF of 2.31 × 10⁻⁵. In gnomAD v4.1, the AF is 1.92 × 10⁻⁵ (0.0019%, 31/1,613,492 alleles, 0 homozygotes) with grpmax FAF of 1.45 × 10⁻⁵. The highest subpopulation frequency is in the Finnish population (AF = 8.09 × 10⁻⁵ in v2.1; 7.89 × 10⁻⁵ in v4.1). All observed frequencies are well below the 0.1% PM2 threshold for non-VCEP generic ACMG adjudication. No homozygotes are observed, consistent with a rare pathogenic variant in a gene where biallelic LoF causes Fanconi anemia.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Moderate

PVS1 · moderate

NM_032444.3:c.5242C>T is a nonsense variant predicted to produce a truncated protein at p.Gln1748Ter (Q1748*). SLX4 loss of function is an established disease mechanism for Fanconi anemia subtype FA-P, and the gene passes the PVS1 gene-level gate. However, the variant is located in the terminal exon (exon 15 of 15), predicting escape from nonsense-mediated decay and production of a protein truncated by only 87 C-terminal amino acids (4.7% of the 1835-residue protein). The truncation removes the C-terminal ~50% of the SLX1-binding domain (SBD, residues 1632–1834), a functionally critical region required for SLX1 interaction and Holliday junction resolvase activity. Under PMC6185798 guidance for last-exon nonsense variants that escape NMD but disrupt a critical functional domain, PVS1 is applied at moderate strength.

PM1Moderate

PM1 · moderate

The variant p.Gln1748Ter is located within the SLX1-binding domain (SBD) of SLX4, a well-characterized critical functional domain spanning residues 1632–1834. The SBD is the extreme C-terminal conserved domain (CCD) that is both necessary and sufficient for SLX1 interaction, and SLX1 binding is required for Holliday junction resolvase activity. Domain mapping was established by systematic co-immunoprecipitation truncation analysis in PMID:19596235 (Fekairi et al. 2009, Figure 2A,C) and PMID:19596236 (Svendsen et al. 2009, Figure 2B, 4E). The nonsense variant truncates the protein within this domain, removing the C-terminal 87 amino acids and disrupting the conserved SBD. No benign missense variation has been observed in this domain in population databases at appreciable frequency. PM1 is met at moderate strength based on location in an experimentally defined, functionally critical protein domain whose disruption is consistent with the established loss-of-function disease mechanism.

PM2Supporting

PM2 · supporting

NM_032444.3:c.5242C>T is absent from or observed at extremely low frequency in large population databases. In gnomAD v2.1, the allele frequency is 3.20 × 10⁻⁵ (0.0032%, 9/281,628 alleles, 0 homozygotes) with grpmax filtering AF of 2.31 × 10⁻⁵. In gnomAD v4.1, the AF is 1.92 × 10⁻⁵ (0.0019%, 31/1,613,492 alleles, 0 homozygotes) with grpmax FAF of 1.45 × 10⁻⁵. The highest subpopulation frequency is in the Finnish population (AF = 8.09 × 10⁻⁵ in v2.1; 7.89 × 10⁻⁵ in v4.1). All observed frequencies are well below the 0.1% PM2 threshold for non-VCEP generic ACMG adjudication. No homozygotes are observed, consistent with a rare pathogenic variant in a gene where biallelic LoF causes Fanconi anemia.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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: PVS1 moderate, PM1 moderate, PM2 supporting; combination = 2 moderate + 1 supporting, 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

31 / 1,613,492 alleles

gnomAD v4.1: 31 / 1,613,492 alleles. Recorded AF 1.9213e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.1957e-05; MAF= 0.00320%, 9/281628 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 8.08604e-05; MAF= 0.00809%, 2/24734 alleles, homozygotes = 0); grpmax FAF= 2.305e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

3 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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: 3 met · 18 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_032444.3:c.5242C>T (p.Gln1748Ter) is a nonsense variant in the terminal exon of SLX4, predicted to produce a truncated protein lacking the C-terminal 87 amino acids within the SLX1-binding domain.

SLX4 loss of function is an established disease mechanism for Fanconi anemia subtype FA-P, meeting the PVS1 gene-level gate.

PVS1 is applied at moderate strength: the variant escapes NMD (terminal exon) but truncates a critical functional domain (SBD, residues 1632–1834), consistent with PMC6185798 guidance.

PM1 is met at moderate strength: the variant is located within the experimentally defined SLX1-binding domain (SBD/CCD, residues 1632–1834), a critical functional domain required for Holliday junction resolvase activity.

PM2 is met at supporting strength: the variant is extremely rare in population databases (gnomAD v2.1 AF = 0.0032%; v4.1 AF = 0.0019%), well below the 0.1% PM2 threshold, with zero homozygotes observed.

No variant-specific functional studies, segregation data, de novo observations, or expert panel classifications were identified. ClinVar reports this variant as Uncertain Significance (Variation ID 864196).

Overall, two moderate criteria (PVS1_moderate + PM1_moderate) and one supporting criterion (PM2_supporting) are met. Under generic ACMG/AMP 2015 combination rules, 2 moderate + 1 supporting criteria do not reach the 'likely pathogenic' threshold, which requires 3 moderate or 2 moderate + 2 supporting. The current evidence profile is consistent with a variant of uncertain significance (VUS), pending additional functional, segregation, or case-control data.

Met · 3

PVS1 ModerateNM_032444.3:c.5242C>T is a nonsense variant predicted to produce a truncated protein at p.Gln1748Ter (Q1748*). SLX4 loss of function is an established disease mechanism for Fanconi anemia subtype FA-P, and the gene passes the PVS1 gene-level gate. However, the variant is located in the terminal exon (exon 15 of 15), predicting escape from nonsense-mediated decay and production of a protein truncated by only 87 C-terminal amino acids (4.7% of the 1835-residue protein). The truncation removes the C-terminal ~50% of the SLX1-binding domain (SBD, residues 1632–1834), a functionally critical region required for SLX1 interaction and Holliday junction resolvase activity. Under PMC6185798 guidance for last-exon nonsense variants that escape NMD but disrupt a critical functional domain, PVS1 is applied at moderate strength. Details ▾Hide ▴

Evidence considered

Nonsense variant p.Gln1748Ter in the last exon of SLX4 (exon 15/15)
SLX4 loss of function is an established disease mechanism (Fanconi anemia FA-P)
Truncation removes C-terminal 87 amino acids within the SLX1-binding domain (SBD
residues 1632-1834)
PMC6185798: last-exon NMD-escape downgraded but critical domain disruption → moderate

Still missing

Whether the remaining SLX4 fragment (1-1747) retains partial SLX1-binding activity is unknown without direct functional testing
No variant-specific functional assay exists for p.Gln1748Ter

Sources

pvs1_generic_framework ↗PMID:19596235 ↗PMID:19596236 ↗PMID:21240275 ↗

PM1 ModerateThe variant p.Gln1748Ter is located within the SLX1-binding domain (SBD) of SLX4, a well-characterized critical functional domain spanning residues 1632–1834. The SBD is the extreme C-terminal conserved domain (CCD) that is both necessary and sufficient for SLX1 interaction, and SLX1 binding is required for Holliday junction resolvase activity. Domain mapping was established by systematic co-immunoprecipitation truncation analysis in PMID:19596235 (Fekairi et al. 2009, Figure 2A,C) and PMID:19596236 (Svendsen et al. 2009, Figure 2B, 4E). The nonsense variant truncates the protein within this domain, removing the C-terminal 87 amino acids and disrupting the conserved SBD. No benign missense variation has been observed in this domain in population databases at appreciable frequency. PM1 is met at moderate strength based on location in an experimentally defined, functionally critical protein domain whose disruption is consistent with the established loss-of-function disease mechanism. Details ▾Hide ▴

Evidence considered

SLX4 SBD/CCD domain mapped to residues 1632-1834 (PMID:19596235
PMID:19596236)
SBD is necessary and sufficient for SLX1 binding and HJ resolvase activity
p.Gln1748Ter truncates within this critical domain
No benign variation in the SBD at appreciable population frequency

Sources

PMID:19596235 ↗PMID:19596236 ↗gnomad_v2 ↗gnomad_v4 ↗

PM2 SupportingNM_032444.3:c.5242C>T is absent from or observed at extremely low frequency in large population databases. In gnomAD v2.1, the allele frequency is 3.20 × 10⁻⁵ (0.0032%, 9/281,628 alleles, 0 homozygotes) with grpmax filtering AF of 2.31 × 10⁻⁵. In gnomAD v4.1, the AF is 1.92 × 10⁻⁵ (0.0019%, 31/1,613,492 alleles, 0 homozygotes) with grpmax FAF of 1.45 × 10⁻⁵. The highest subpopulation frequency is in the Finnish population (AF = 8.09 × 10⁻⁵ in v2.1; 7.89 × 10⁻⁵ in v4.1). All observed frequencies are well below the 0.1% PM2 threshold for non-VCEP generic ACMG adjudication. No homozygotes are observed, consistent with a rare pathogenic variant in a gene where biallelic LoF causes Fanconi anemia. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.0032%
9/281
628 alleles
0 homozygotes
gnomAD v4.1: AF=0.0019%
31/1
613
492 alleles
Well below PM2 threshold of <0.1%

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 18 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change as an established pathogenic variant. No pathogenic or likely pathogenic ClinVar variant at p.Gln1748 was identified in the PM5 candidate search and no literature reports of a pathogenic missense at this codon were found. Details ▾Hide ▴

Evidence considered

No pathogenic variant at p.Gln1748 identified in ClinVar or literature
PM5 candidate search returned zero same-residue comparator variants

Sources

clinvar ↗pm5_candidates

PS2 PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. No de novo data for NM_032444.3:c.5242C>T were identified in ClinVar, literature, or any other source. Details ▾Hide ▴

Evidence considered

No de novo reports identified in any reviewed source

Still missing

De novo status has not been evaluated for this variant

PS3 PS3 requires well-established functional studies showing a damaging effect for the variant or a systematically characterized range that includes this position. While SLX4 functional domains are well-characterized in the literature (the SLX1-binding domain was mapped to residues 1632–1834 by PMID:19596235, and Holliday junction resolvase activity depends on the C-terminal CCD domain as shown in PMID:19596236), no variant-specific functional assay has been performed on p.Gln1748Ter. The published functional studies characterized domain-level interactions via truncation mapping, not systematic saturation mutagenesis or tiling screens covering position 1748. Domain-level inference from sparse testing qualifies for PM1, not PS3. In accordance with the PS3 calibration rules, domain-level evidence from a limited set of truncation constructs without systematic characterization of each individual residue in the range does not satisfy PS3. Details ▾Hide ▴

Evidence considered

SLX4 SBD mapped to residues 1632-1834 by co-immunoprecipitation truncation analysis (PMID:19596235)
C-terminal CCD domain shown sufficient for SLX1 binding and HJ resolution (PMID:19596236)
No variant-specific functional assay for p.Gln1748Ter
No systematic saturation mutagenesis or tiling screen covering position 1748

Still missing

Direct functional testing of p.Gln1748Ter would be needed to confirm loss of SLX1 binding and HJ resolvase activity

Sources

PMID:19596235 ↗PMID:19596236 ↗

PS4 PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls. No case-control data, cohort studies enumerating this variant, or significant patient counts were identified in ClinVar or the reviewed literature. The variant is present at very low frequency in gnomAD (AF ~0.003%) but no comparable affected-population frequency data exist. Details ▾Hide ▴

Evidence considered

Variant reported as VUS in ClinVar by 3 clinical labs without patient count enrichment data
No published cohort studies enumerating this variant in affected vs. control populations

Still missing

Case-control data not available

Sources

clinvar ↗gnomad_v2 ↗gnomad_v4 ↗

PM6 PM6 requires a de novo observation without confirmation of paternity and maternity. No de novo reports for NM_032444.3:c.5242C>T were identified in ClinVar submissions, literature, or any other reviewed source. Details ▾Hide ▴

Evidence considered

No de novo observations reported

Still missing

De novo status has not been evaluated

PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for this variant in ClinVar or the reviewed literature. Details ▾Hide ▴

Evidence considered

No segregation data available

Still missing

Family studies not available

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. SpliceAI predicts no significant splicing impact (max delta score = 0.02). REVEL score is not available for this variant. BayesDel score is 0.34181, which exceeds the recommended threshold of 0.27 for a deleterious prediction but is in a borderline range and represents only a single in silico predictor. HCI prior is not available for SLX4. With only one predictive tool providing a borderline score and SpliceAI showing no splicing effect, the multiple lines of computational evidence required for PP3 are not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.02 (no splicing impact)
BayesDel = 0.34181 (borderline deleterious)
REVEL not available
HCI prior not available for SLX4
Only one predictor with borderline score
lacks multiple concordant lines of evidence

Still missing

REVEL score unavailable for this genomic position

Sources

spliceai ↗bayesdel

PP4 PP4 requires the variant to be identified in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. No patient-specific phenotype data are available for this variant in ClinVar or the reviewed literature. The ClinVar submissions do not include detailed phenotype information. Details ▾Hide ▴

Evidence considered

No patient phenotype data available
ClinVar submissions lack specific phenotype annotations

Still missing

Patient phenotype data not reported in available sources

Sources

clinvar ↗

PP5 PP5 requires a reputable source (e.g., clinical laboratory with recognized expertise) to have recently reported the variant as pathogenic. In ClinVar, NM_032444.3:c.5242C>T is classified as Uncertain Significance by all three submitting laboratories (Fulgent Genetics, Labcorp/Invitae, University of Chicago). The review status is 'criteria provided, single submitter' (not expert panel). Under the global PP5 rule requiring ClinVar 3-star expert panel classification, this variant does not meet the threshold. No expert panel has reviewed this variant. Details ▾Hide ▴

Evidence considered

ClinVar classification: Uncertain Significance (Variation ID 864196)
Review status: criteria provided
single submitter (not 3-star expert panel)
No expert panel classification available

Sources

clinvar ↗

BA1 BA1 requires allele frequency >1% in any population database. gnomAD v2.1 AF = 0.0032% (9/281,628), v4.1 AF = 0.0019% (31/1,613,492). The highest subpopulation AF is 0.0081% in Finnish (v2.1). All observed frequencies are orders of magnitude below the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.0032%
gnomAD v4.1: AF=0.0019%
Highest subpopulation AF: 0.0081% (Finnish
v2.1)
All frequencies <<1%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 BS1 requires allele frequency >0.3% (non-VCEP generic ACMG threshold). gnomAD v2.1 AF = 0.0032%, v4.1 AF = 0.0019%, with highest subpopulation AF of 0.0081% (Finnish). All observed frequencies are far below the 0.3% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.0032%
v4.1 AF=0.0019%
All frequencies <<0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 BS2 requires observation of the variant in a healthy adult in the homozygous state, or in trans with a pathogenic variant for a fully penetrant dominant disorder. No homozygotes are observed in gnomAD v2.1 (0/281,628) or v4.1 (0/1,613,492). No such observations were reported in ClinVar or the reviewed literature. Details ▾Hide ▴

Evidence considered

gnomAD: 0 homozygotes in ~1.9 million alleles across v2.1+v4.1
No homozygous observations reported in any source

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 BS3 requires well-established functional studies showing no deleterious effect. No functional studies testing NM_032444.3:c.5242C>T specifically have been performed. The domain-level functional characterization of SLX4 (PMID:19596235, PMID:19596236) demonstrated that the C-terminal SBD/CCD domain is critical for SLX1 binding and HJ resolvase activity, which is consistent with a deleterious effect of truncation within this domain rather than a benign effect. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies have been performed
Domain functional data are consistent with deleterious
not benign
effect

Still missing

No direct functional testing of the variant

Sources

PMID:19596235 ↗PMID:19596236 ↗

BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No segregation data are available for this variant in any reviewed source. Details ▾Hide ▴

Evidence considered

No segregation data available

Still missing

Family studies not available

BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. SLX4-associated disease (Fanconi anemia) is autosomal recessive. No co-occurrence data in trans or cis are available for this variant. Details ▾Hide ▴

Evidence considered

No trans or cis observation data available
SLX4 disease (Fanconi anemia FA-P) is autosomal recessive

Still missing

Phase information not available

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. SpliceAI predicts no splicing impact (max delta = 0.02), satisfying one line of benign computational evidence. However, BayesDel scores the variant at 0.34181, exceeding the pathogenic threshold of 0.27 and contradicting a benign prediction. With conflicting in silico evidence (one benign, one deleterious), the requirement for multiple concordant lines of benign computational evidence is not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.02 (benign)
BayesDel = 0.34181 (deleterious
>0.27 threshold)
Conflicting computational predictions preclude BP4

Still missing

REVEL score unavailable
could provide additional resolution

Sources

spliceai ↗bayesdel

BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant in ClinVar or the reviewed literature. Details ▾Hide ▴

Evidence considered

No alternate molecular diagnosis reported in cases with this variant

Still missing

Alternate molecular basis not investigated in reported cases

BP6 BP6 requires a reputable source to report the variant as benign. ClinVar classification is Uncertain Significance (Variation ID 864196) from all three submitting laboratories. No source reports this variant as benign or likely benign. Details ▾Hide ▴

Evidence considered

ClinVar classification: Uncertain Significance
No benign classification from any source

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PM3 N/APM3 requires observation in trans with a pathogenic variant; no phase data available for this variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants; not applicable to a nonsense substitution variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense variant at the same amino acid residue. The variant p.Gln1748Ter is a nonsense change, not a missense. Furthermore, the automated PM5 candidate search found zero ClinVar variants at codon 1748 with any pathogenic classification, and classic same-residue PM5 semantics could not be confirmed. As a terminal truncation near the C-terminus rather than a missense at a residue with a known pathogenic alternative, PM5 does not apply. Details ▾Hide ▴

Evidence considered

Variant is a nonsense
not a missense substitution at a codon with a known pathogenic missense
No ClinVar pathogenic or likely pathogenic variants at codon 1748 identified
PM5 candidate search returned zero candidates

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes where missense variation is a known disease mechanism and benign missense variation is rare. NM_032444.3:c.5242C>T is a nonsense (truncating) variant, not a missense variant. PP2 is not applicable. Details ▾Hide ▴

Evidence considered

Variant is a nonsense variant
PP2 is restricted to missense variants

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_032444.3:c.5242C>T is itself a truncating (nonsense) variant, not a missense variant. BP1 is therefore not applicable. Details ▾Hide ▴

Evidence considered

Variant is a nonsense (truncating) variant
BP1 is restricted to missense variants

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_032444.3:c.5242C>T is a nonsense (stop-gain) variant, not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Variant is a nonsense variant
BP7 is restricted to synonymous variants

Sources

spliceai ↗

PS5 N/APS5 is not a criterion defined in the standard ACMG/AMP 2015 framework (Richards et al., PMID:25741868). The standard pathogenic criteria are PVS1, PS1–PS4, PM1–PM6, and PP1–PP5. No VCEP/CSPEC framework overrides this for SLX4. Details ▾Hide ▴

Evidence considered

PS5 is not a standard ACMG/AMP criterion

Sources

PMID:25741868 ↗

Identifiers

Gene: SLX4
Transcript: NM_032444.3
Coding (HGVS c.): NM_032444.3:c.5242C>T
Protein (HGVS p.): NP_115820.2:p.(Gln1748Ter)
GRCh38: chr16:3582605 G>A
GRCh37: chr16:3632606 G>A
ClinVar: 864196

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 31 / 1,613,492 alleles AF 1.92e-05 · 0 homozygotes · FAF 1.45e-05

gnomAD v2.1 9 / 281,628 alleles AF 3.2e-05 · 0 homozygotes · FAF 2.31e-05

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-05 · 31 / 1,613,492 alleles · 0 hom · FAF 1.5e-05

European (Finnish)5 / 63,410	7.9e-05
European (non-Finnish)25 / 1,180,048	2.1e-05
Remaining individuals1 / 62,484	1.6e-05

0 alternate alleles recorded in 7 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 3.2e-05 · 9 / 281,628 alleles · 0 hom · FAF 2.3e-05

European (Finnish)2 / 24,734	8.1e-05
European (non-Finnish)7 / 128,472	5.4e-05

0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.9213e-05; MAF= 0.00192%, 31/1613492 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 7.88519e-05; MAF= 0.00789%, 5/63410 alleles, homozygotes = 0); grpmax FAF= 1.454e-05.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +54 bp

0.020

SpliceAI acceptor gainat -231 bp

0.010

SpliceAI donor lossat -78 bp

0.020

SpliceAI donor gainat +169 bp

0.000

Pangolin splice lossmagnitude shown

-0.030

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: 0.342

How the predictions were used

Evidence considered

SpliceAI max delta = 0.02 (no splicing impact)
BayesDel = 0.34181 (borderline deleterious)
REVEL not available
HCI prior not available for SLX4
Only one predictor with borderline score
lacks multiple concordant lines of evidence

Still missing

REVEL score unavailable for this genomic position

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta = 0.02 (benign)
BayesDel = 0.34181 (deleterious
>0.27 threshold)
Conflicting computational predictions preclude BP4

Still missing

REVEL score unavailable
could provide additional resolution

Sources

spliceai ↗bayesdel

Evidence considered

Variant is a nonsense variant
BP7 is restricted to synonymous variants

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.34181.

8 paper records listed. 3 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair.

Characterized SLX4/BTBD12 as a mammalian ortholog of yeast Slx4p that assembles a Holliday junction resolvase complex. Mapped the SLX1-binding domain (SBD) to the extreme C-terminus of SLX4 (residues 1632–1834) using systematic co-immunoprecipitation truncation analysis, and demonstrated that SLX4-SLX1 interaction is required for symmetrical HJ cleavage. NM_032444.3:c.5242C>T (p.Gln1748Ter) was not identified in this paper.
→ PVS1 → PM1 Does not name this variant
PMID 19596235 ↗
Source detail

SLX1 associated with the extreme C-terminus of SLX4 (residues 1632–1834) (Figure 2A, C), a region displaying the highest conservation between yeast Slx4p, MUS312, and vertebrate SLX4 (Figure 2I), which we refer to hereafter as the SLX1-binding domain (SBD).

Location Figure 2A,C (SBD domain mapping); Results section 'Structural anatomy of the SLX4 complex'

Context Co-immunoprecipitation in HEK293T cells, in vitro HJ cleavage assays with recombinant SLX1-SLX4 SBD complex
Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.

Identified human SLX4 as a Holliday junction resolvase subunit that binds multiple DNA repair endonucleases. Demonstrated that the C-terminal CCD domain of SLX4 (corresponding to the SBD) is both necessary and sufficient for SLX1 binding and HJ resolvase activity, and that the SAP domain mediates MUS81 binding. NM_032444.3:c.5242C>T (p.Gln1748Ter) was not identified in this paper.
→ PVS1 → PM1 Does not name this variant
PMID 19596236 ↗
Source detail

Robust HJ resolution was observed even with the shortest C-terminal SLX4-7 fragment consisting of just the CCD domain of SLX4 (Figure 4E).

Location Figure 2B (CCD/SLX1 interaction), Figure 4E (C-terminal SLX4-7 fragment HJ resolution)

Context Y2H interaction assays, co-immunoprecipitation in HEK293 cells, in vitro HJ resolution assays
Mutations of the SLX4 gene in Fanconi anemia.

Identified biallelic SLX4 mutations in two patients with Fanconi anemia, establishing SLX4 as a new FA gene (FANCP/FA-P). The paper characterized SLX4 as a multidomain scaffold protein interacting with SLX1, ERCC4/XPF-ERCC1, and MUS81-EME1 nucleases. NM_032444.3:c.5242C>T (p.Gln1748Ter) was not among the mutations identified in this study.
→ PVS1 Does not name this variant
PMID 21240275 ↗
Source detail

SLX4 is a multidomain scaffold protein interacting with three distinct nucleases SLX1, ERCC4/XPF-ERCC1, and MUS81-EME1.

Location Results section describing patient mutations

Context Patient-derived cell lines, complementation assays with wild-type SLX4

Other recorded publications

Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair.

Identified human SLX4 as a scaffold protein for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1. The paper characterized SLX4 as a BTB-domain-containing protein that coordinates structure-specific endonucleases required for DNA repair. NM_032444.3:c.5242C>T (p.Gln1748Ter) was not identified in this paper.
Does not name this variant
PMID 19595721 ↗
Low prevalence of SLX4 loss-of-function mutations in non-BRCA1/2 breast and/or ovarian cancer families.

Screened for SLX4 loss-of-function mutations in non-BRCA1/2 breast and ovarian cancer families and found a low prevalence. NM_032444.3:c.5242C>T (p.Gln1748Ter) was not identified in this paper.
Does not name this variant
PMID 23211700 ↗
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

Standards and guidelines for the interpretation of sequence variants (ACMG/AMP 2015 consensus recommendations). This is a framework-level reference that provides criteria definitions and classification rules; it does not discuss specific variants. NM_032444.3:c.5242C>T was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
Carrier screening in individuals of Ashkenazi Jewish descent.

Gross SJ et al. · 2008

ACMG practice guideline on carrier screening in individuals of Ashkenazi Jewish descent. Discusses Tay-Sachs disease, Canavan disease, cystic fibrosis, familial dysautonomia, and other Jewish genetic disorders. SLX4 and NM_032444.3:c.5242C>T are not mentioned. Fanconi anemia group C is referenced but only in the context of FANCC, not SLX4/FANCP.
Does not name this variant
PMID 18197057 ↗
ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.

2009

ACOG Committee Opinion on preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Lists recessive disorders prevalent in Ashkenazi Jews (Tay-Sachs, Canavan, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, etc.). SLX4 and NM_032444.3:c.5242C>T are not mentioned.
Does not name this variant
PMID 19888064 ↗

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

gnomAD v4.1 31 / 1,613,492 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗

ClinVar 3 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

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 864196)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.34181.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.