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RECQL4c.2296delLikely pathogenic
Print report
Variant interpretation report

RECQL4 c.2296del, p.(Arg766GlyfsTer77)

NM_004260.4:c.2296del NP_004251.4:p.(Arg766GlyfsTer77) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RECQL4

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

This variant is a frameshift deletion predicted to cause p.(Arg766GlyfsTer77). RECQL4 loss of function is supported as a germline disease mechanism, and the generic PVS1 framework is applicable. The predicted premature termination occurs well upstream of the last exon-exon junctions, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. The observed population frequency is 0, which is below the 0.1% threshold used for rarity support in this non-VCEP review and supports PM2.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.150 maximum delta

Recorded SpliceAI maximum delta score: 0.150. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

3 Benign.

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.

28 criteria with recorded statuses: 2 met · 6 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The RECQL4 c.2296del (p.Arg766GlyfsTer77) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Benign by 3 single-submitter clinical laboratory submissions.

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity for a RECQL4 germline variant.

This deletion causes a frameshift with premature termination, and the generic PVS1 framework supports loss-of-function interpretation because RECQL4 loss of function is an established germline disease mechanism.

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.15, and missense-oriented predictors such as REVEL and BayesDel are not applicable to this deletion.

Met · 2

PVS1 Very strongThis variant is a frameshift deletion predicted to cause p.(Arg766GlyfsTer77). RECQL4 loss of function is supported as a germline disease mechanism, and the generic PVS1 framework is applicable. The predicted premature termination occurs well upstream of the last exon-exon junctions, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 framework for loss-of-function variants
Evidence considered
  • Frameshift consequence p.(Arg766GlyfsTer77)
  • RECQL4 loss-of-function mechanism supported
  • Predicted truncation occurs before the terminal exons
Still missing
  • Direct disease-specific RECQL4 loss-of-function guidance was not available from an official VCEP or local gene framework.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. The observed population frequency is 0, which is below the 0.1% threshold used for rarity support in this non-VCEP review and supports PM2. Details ▾Hide ▴
Rule
Population rarity below 0.1% threshold
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PS4 Available evidence does not show enrichment of this variant in affected individuals over controls. The variant has a ClinVar record, but no case-control dataset or published excess of affected carriers was identified. Details ▾Hide ▴
Evidence considered
  • ClinVar record present without enrichment data
Still missing
  • Published affected case counts and comparator control data were not identified.
Sources
clinvar ↗PMID:20301383 ↗PMID:20301415 ↗
PM1 Available evidence does not support this variant lying in a mutational hotspot or a well-established critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • No statistically significant hotspot identified
Still missing
  • A domain-specific RECQL4 framework was not available.
Sources
hotspots ↗PMID:12734318 ↗PMID:15897384 ↗PMID:18716613 ↗PMID:23842644 ↗PMID:28481359 ↗
PP5 PP5 is not applied. The available ClinVar record does not provide an expert-panel pathogenic assertion that can be used as independent supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • ClinVar review status is single submitter
  • not expert panel
Sources
clinvar ↗
BA1 This variant is absent from available population datasets. The observed population frequency is 0, which is below the 1% threshold for BA1 and does not support a stand-alone benign criterion. Details ▾Hide ▴
Rule
BA1 requires frequency above 1%
Evidence considered
  • Population frequency 0 in reviewed datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from available population datasets. The observed population frequency is 0, which is below the 0.3% threshold used for BS1 in this non-VCEP review and does not support BS1. Details ▾Hide ▴
Rule
BS1 requires frequency above 0.3%
Evidence considered
  • Population frequency 0 in reviewed datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP6 BP6 is not applied. Although ClinVar lists this variant as Benign, the available submissions are single-submitter clinical laboratory assertions without expert-panel review, so they are not sufficient as stand-alone benign evidence here. Details ▾Hide ▴
Evidence considered
  • ClinVar benign assertions from 3 single-submitter laboratory submissions
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo evidence identified
Still missing
  • Case-level trio data were not identified.
PS3 No well-established variant-specific functional study demonstrating a damaging effect for this exact deletion was identified from the available evidence. Details ▾Hide ▴
Evidence considered
  • Curated literature leads were identified
  • but no directly established variant-specific assay result was available here
Still missing
  • Direct review of any exact variant functional assay data would be needed before applying PS3.
Sources
oncokb ↗PMID:12734318 ↗PMID:15897384 ↗PMID:18716613 ↗PMID:23842644 ↗PMID:28481359 ↗
PM3 RECQL4-related disease is consistent with a recessive mechanism, but no observation of this variant in trans with a pathogenic RECQL4 variant was identified. Details ▾Hide ▴
Evidence considered
  • No in trans observation identified
Still missing
  • Phase-resolved biallelic case data were not identified.
PM6 No presumed de novo report was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No presumed de novo evidence identified
Still missing
  • Family-based origin data were not identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation evidence identified
Still missing
  • Pedigree-level segregation information was not identified.
PP4 No phenotype-specific clinical evidence was identified showing a presentation highly specific for a RECQL4-related disorder in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
  • No specific phenotype correlation identified
Still missing
  • Phenotype-level case details were not identified.
BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency inconsistent with disease penetrance. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier evidence identified
Still missing
  • Control observations with phenotype context were not identified.
BS3 No well-established variant-specific functional study demonstrating a normal effect for this exact deletion was identified. Details ▾Hide ▴
Evidence considered
  • No directly established benign functional result for the exact variant was available here
Still missing
  • Direct review of any exact variant benign functional data would be needed before applying BS3.
Sources
oncokb ↗PMID:12734318 ↗PMID:15897384 ↗PMID:18716613 ↗PMID:23842644 ↗PMID:28481359 ↗
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No non-segregation evidence identified
Still missing
  • Family studies demonstrating lack of segregation were not identified.
BP2 No phase-resolved observation was identified showing this variant in cis with another pathogenic variant or in trans with a pathogenic variant for a fully penetrant dominant condition. Details ▾Hide ▴
Evidence considered
  • No qualifying BP2 phase evidence identified
Still missing
  • Allelic phase data were not identified.
BP5 No alternate molecular explanation was identified that would make this variant an incidental finding for the observed phenotype. Details ▾Hide ▴
Evidence considered
  • No alternate-cause evidence identified
Still missing
  • Detailed phenotype and alternative-cause data were not identified.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this variant is a frameshift deletion and not an alternate nucleotide change producing the same amino acid substitution as a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
Sources
pvs1_variant_assessment
PM4 N/APM4 is not applicable because this variant is a frameshift predicted to introduce a premature stop codon and is more appropriately assessed under PVS1 rather than as an in-frame protein length change. Details ▾Hide ▴
Evidence considered
  • Frameshift with premature termination
Sources
pvs1_variant_assessment
PM5 N/APM5 is not applicable because this variant is not a missense change, and the available PM5 review did not support use of classic same-residue PM5 logic for this deletion. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found no applicable same-residue missense comparators
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
PP3 N/APP3 is not applied because this variant is a frameshift deletion rather than a missense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.15. REVEL and BayesDel are not applicable to this deletion. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.15
  • REVEL not applicable
  • BayesDel not applicable
Sources
spliceai ↗
BP1 N/ABP1 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
BP3 N/ABP3 is not applicable because this variant is not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
BP4 N/ABP4 is not applied because this frameshift deletion already predicts substantial protein disruption, and SpliceAI showing no significant splice impact with a maximum delta score of 0.15 does not provide benign computational evidence against the frameshift effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.15
Sources
spliceai ↗
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor a deep intronic change. Details ▾Hide ▴
Evidence considered
  • Variant type is coding frameshift deletion

Identifiers

Gene
RECQL4
Transcript
NM_004260.4
Coding (HGVS c.)
NM_004260.4:c.2296del
Protein (HGVS p.)
NP_004251.4:p.(Arg766GlyfsTer77)
GRCh38
chr8:144513384 CG>C
GRCh37
chr8:145738767 CGG>C
ClinVar
1327943

Gene diagram

Every interpreted variant in RECQL4, mapped onto the exon structure of NM_004260.4. Select a row to find it on the plot.

RECQL4NM_004260.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -235 bp
0.020
SpliceAI acceptor gainat -161 bp
0.030
SpliceAI donor lossat -166 bp
0.010
SpliceAI donor gainat +33 bp
0.150
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 is not applied because this variant is a frameshift deletion rather than a missense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.15. REVEL and BayesDel are not applicable to this deletion. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.15
  • REVEL not applicable
  • BayesDel not applicable
Sources
spliceai ↗
BP4 N/ABP4 is not applied because this frameshift deletion already predicts substantial protein disruption, and SpliceAI showing no significant splice impact with a maximum delta score of 0.15 does not provide benign computational evidence against the frameshift effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.15
Sources
spliceai ↗
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor a deep intronic change. Details ▾Hide ▴
Evidence considered
  • Variant type is coding frameshift deletion

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).

8 paper records 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

  • Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
    No paper-specific finding is recorded.
    PMID 12734318 ↗
  • A patient with Rothmund-Thomson syndrome and all features of RAPADILINO.
    No paper-specific finding is recorded.
    PMID 15897384 ↗
  • The mutation spectrum in RECQL4 diseases.
    No paper-specific finding is recorded.
    PMID 18716613 ↗
  • DNA helicases involved in DNA repair and their roles in cancer.
    No paper-specific finding is recorded.
    PMID 23842644 ↗
  • Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
    No paper-specific finding is recorded.
    PMID 28481359 ↗
  • 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
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Baller-Gerold Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301383 ↗
  • Rothmund-Thomson Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301415 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.150 Open source ↗
ClinVar 3 Benign 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 1327943)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).

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.