NM_004260.3:c.2569_2574del

RECQL4 · NP_004251.3:p.(Cys857_Thr858del) · NM_004260.3

GRCh37: chr8:145738410 TGGTGCA>T · GRCh38: chr8:144513027 TGGTGCA>T

Gene: RECQL4 Transcript: NM_004260.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP6 supporting benign

Variant details

Gene

RECQL4

Transcript

NM_004260.3

Protein

NP_004251.3:p.(Cys857_Thr858del)

gnomAD AF

0.0015745080853117894 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004260.3:c.2569_2574del (p.Cys857_Thr858del) is an in-frame deletion of 6 nucleotides in exon 15 of RECQL4, encoding a DNA helicase associated with Rothmund-Thomson syndrome (autosomal recessive) and cancer predisposition.

This variant is present at high frequency in the general population: gnomAD v2.1 reports 1462 alleles out of 218,994 (0.67%) with 30 homozygotes, and a grpmax filtering allele frequency of 3.9% in the Admixed American population. gnomAD v4.1 reports 2479 alleles out of 1,574,460 (0.16%) with 41 homozygotes. The presence of 30 or more healthy homozygotes in population databases is incompatible with pathogenicity for a severe autosomal recessive disorder.

The variant meets BA1 (stand-alone benign): allele frequency exceeds 1% in the general population (grpmax FAF 3.9% in gnomAD v2.1). It also meets BS1 (strong benign): allele frequency exceeds 0.3% (global AF 0.67% in gnomAD v2.1), and BS2 (strong benign): 30 homozygotes are observed in a population database for a recessive disorder expected to be fully penetrant at an early age.

ClinVar reports this variant as Benign by 8 clinical laboratories and Likely benign by 1 laboratory (variation ID 135140), meeting BP6 (supporting benign).

No pathogenic criteria are met. PVS1 is not applicable as this is an in-frame deletion, not a null variant. No functional data (PS3), segregation data (PP1), or case-control data (PS4) support pathogenicity. All in silico evidence (SpliceAI delta 0.00; REVEL/BayesDel unavailable for deletion variants) is neutral. PM2 is not met due to the variant's high population frequency.

Classification: BENIGN. BA1 alone is sufficient for a benign classification per ACMG/AMP 2015 guidelines. The combination of BA1 + BS1 + BS2 + BP6 provides overwhelming evidence of benignity.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Not met	NM_004260.3:c.2569_2574del is an in-frame deletion of 6 nucleotides removing residues Cys857 and Thr858. It does not fall into the default PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants) per ClinGen SVI PVS1 recommendations (PMC6185798). The generic PVS1 framework does not apply to in-frame deletions.	pvs1_generic_framework
PS1	N/A	This is an in-frame deletion, not a single nucleotide change. PS1 requires a different nucleotide change at the same position with a pathogenic classification.
PS2	Not assessed	No de novo data available for this variant.
PS3	Not met	No variant-specific functional data identified for NM_004260.3:c.2569_2574del. OncoKB reports unknown oncogenic effect with no variant-specific publications. The one paper flagged for PS3 screening (PMID:24728327) does not mention this variant.	oncokb
PS4	Not met	This variant is present at high frequency in the general population (gnomAD v2.1 AF 0.67%, 30 homozygotes), which is inconsistent with pathogenicity. No case-control enrichment data are available, and the variant's prevalence in population databases argues against disease association.	gnomad_v2 gnomad_v4
PS5	N/A	This is an in-frame deletion, not a single nucleotide change. PS5 requires a different nucleotide change at the same position that is reported as pathogenic.
PM1	Not met	This variant is not located in a statistically significant mutational hotspot (cancerhotspots.org). While RECQL4 has a characterized helicase domain, the deleted residues (C857-T858) are not in a well-characterized critical functional domain with evidence that disruption causes disease. No residue-specific functional domain characterization was identified for this position.	oncokb
PM2	Not met	This variant is present at high frequency in gnomAD (v2.1 AF 0.67%, v4.1 AF 0.16%), far exceeding the PM2 threshold of <0.1% for a recessive gene. The variant is not rare in population databases, with 30 homozygotes in v2.1.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped by instruction — PM3 is trivially not applicable.
PM4	Not met	Although this is an in-frame deletion causing a protein length change (loss of 2 residues), the variant is present at high frequency in the general population (gnomAD v2.1 AF 0.67%, 30 homozygotes), which is inconsistent with a pathogenic protein-length-altering variant in a recessive disease gene. The high population frequency overrides the technical eligibility for PM4.	gnomad_v2 gnomad_v4
PM5	N/A	This is an in-frame deletion, not a missense variant. PM5 requires a different missense change at the same residue reported as pathogenic. The pm5_candidates module confirmed no classic same-residue PM5 semantics are applicable for this deletion.
PM6	Not assessed	No de novo data available for this variant.
PP1	Not assessed	No segregation data available for this variant.
PP2	N/A	This is an in-frame deletion, not a missense variant. PP2 applies only to missense variants in genes with low rates of benign missense variation.
PP3	Not met	No in silico evidence supports a deleterious effect. SpliceAI predicts no splicing impact (max delta score 0.00). REVEL and BayesDel scores are unavailable as these tools are designed for single nucleotide variants, not in-frame deletions. No HCI prior score is available for RECQL4.	spliceai
PP4	Not assessed	No patient phenotype data available for assessment.
PP5	Not met	ClinVar reports this variant as Benign (8 clinical laboratories) and Likely benign (1 clinical laboratory), not pathogenic. PP5 requires a reputable source to report the variant as pathogenic. The ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the threshold for PP5 application even if the classification were pathogenic.	clinvar
BA1	Met	This variant is present at high frequency in the general population. The grpmax filtering allele frequency in gnomAD v2.1 is 3.9% (Admixed American population), exceeding the BA1 threshold of >1%. Additionally, 30 homozygotes are observed in gnomAD v2.1 and 41 in v4.1, which is incompatible with a pathogenic variant causing Rothmund-Thomson syndrome (autosomal recessive, severe early-onset disorder).	gnomad_v2 gnomad_v4
BS1	Met	This variant is present in gnomAD v2.1 at an allele frequency of 0.67%, exceeding the BS1 threshold of >0.3% for general population frequency. This frequency is inconsistent with a pathogenic variant causing Rothmund-Thomson syndrome.	gnomad_v2
BS2	Met	Thirty homozygotes are observed in gnomAD v2.1 and 41 homozygotes in gnomAD v4.1. RECQL4 causes Rothmund-Thomson syndrome (autosomal recessive), a severe disorder with full penetrance expected at an early age. The presence of multiple apparently healthy homozygous adults in a population database is strong evidence that this variant is benign.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation with disease is available.
BP1	N/A	This is an in-frame deletion, not a missense variant. BP1 applies only to missense variants in genes where primarily truncating variants cause disease.
BP2	Not assessed	No cis/trans phase data are available for this variant.
BP3	Not met	This is an in-frame deletion of two amino acids. There is no evidence that the deleted region (C857-T858) falls within a repetitive region without known function. The deletion removes residues from the RECQL4 protein and a functional consequence cannot be excluded based on location in a repetitive region.
BP4	Not met	SpliceAI predicts no splicing impact (max delta score 0.00), but this represents only a single line of computational evidence. BP4 requires multiple lines of computational evidence suggesting no impact. REVEL and BayesDel are unavailable for this deletion variant, and no other in silico tools provide evidence of a benign effect.	spliceai
BP5	N/A	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. Not applicable here as the variant itself is under investigation.
BP6	Met	This variant has been reported in ClinVar as Benign by 8 clinical laboratories and as Likely benign by 1 clinical laboratory (ClinVar variation ID 135140). Although the aggregate review status is 'criteria provided, single submitter' (1-star), the consistent classification across multiple independent clinical laboratories supports a benign interpretation at supporting strength level.	clinvar
BP7	N/A	This is an in-frame deletion, not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.