NM_004260.4:c.2296del

RECQL4 · NP_004251.4:p.(Arg766GlyfsTer77) · NM_004260.4

GRCh37: chr8:145738767 CGG>C · GRCh38: chr8:144513384 CG>C

Gene: RECQL4 Transcript: NM_004260.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

RECQL4

Transcript

NM_004260.4

Protein

NP_004251.4:p.(Arg766GlyfsTer77)

gnomAD AF

ClinVar

Benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 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.	pvs1_variant_assessment
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant.
PS3	Not assessed	No well-established variant-specific functional study demonstrating a damaging effect for this exact deletion was identified from the available evidence.	oncokb PMID:12734318 PMID:15897384 PMID:18716613 PMID:23842644 PMID:28481359
PS4	Not met	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.	clinvar
PM1	Not met	Available evidence does not support this variant lying in a mutational hotspot or a well-established critical functional domain without benign variation.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	RECQL4-related disease is consistent with a recessive mechanism, but no observation of this variant in trans with a pathogenic RECQL4 variant was identified.
PM4	N/A	PM4 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.	pvs1_variant_assessment
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	No presumed de novo report was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is not applicable because this variant is not a missense change.
PP3	N/A	PP3 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.	spliceai
PP4	Not assessed	No phenotype-specific clinical evidence was identified showing a presentation highly specific for a RECQL4-related disorder in an individual carrying this variant.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a frequency inconsistent with disease penetrance.
BS3	Not assessed	No well-established variant-specific functional study demonstrating a normal effect for this exact deletion was identified.	oncokb PMID:12734318 PMID:15897384 PMID:18716613 PMID:23842644 PMID:28481359
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is not applicable because this variant is not a missense change.
BP2	Not assessed	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.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame deletion or insertion in a repetitive region.
BP4	N/A	BP4 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.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified that would make this variant an incidental finding for the observed phenotype.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 is not applicable because this variant is neither synonymous nor a deep intronic change.

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