RECQL4 c.738_801delinsTATCCGTGTGGGGAGCCCCCAGCCCAGCAGCAGTGGAGGCGAGAAGCGGAGATGGAACGAGGAC, p.Glu267Asp
NM_004260.4:c.738_801delinsTATCCGTGTGGGGAGCCCCCAGCCCAGCAGCAGTGGAGGCGAGAAGCGGAGATGGAACGAGGAC
Variant of Uncertain Significance (VUS)
RECQL4 E267D is absent from population databases (PM2) and predicted benign by computational and gene mechanism criteria (BP1, BP4). There is no functional, segregation, or case‐control evidence to support pathogenicity. The conflicting moderate pathogenic and supporting benign evidence yields a classification of VUS.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
RECQL4
Transcript
NM_004260.4
MANE Select
Total Exons
21
Strand
Reverse (−)
Reference Sequence
NC_000008.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004260.3 | RefSeq Select | 21 exons | Reverse |
| NM_004260.2 | Alternative | 21 exons | Reverse |
| NM_004260.1 | Alternative | 21 exons | Reverse |
Variant Details
HGVS Notation
NM_004260.4:c.738_801delinsTATCCGTGTGGGGAGCCCCCAGCCCAGCAGCAGTGGAGGCGAGAAGCGGAGATGGAACGAGGAC
Protein Change
E267D
Location
Exon 5
(Exon 5 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 267 in gene RECQL4
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.738_801delinsTATCCGTGTGGGGAGCCCCCAGCCCAGCAGCAGTGGAGGCGAGAAGCGGAGATGGAACGAGGAC
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 267 in gene RECQL4
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: 'This is a missense (E267D) variant, not a null variant.' Therefore, this criterion is not applied at Not Applied strength because the variant is not predicted to cause loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: 'No previously established pathogenic variant at E267 resulting in D.' Therefore, this criterion is not applied at Not Applied strength because there is no matching known pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: 'No parental or inheritance information provided.' Therefore, this criterion is not applied at Not Applied strength due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: 'No functional studies have been performed.' Therefore, this criterion is not applied at Not Applied strength because functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: 'No case–control or cohort data available.' Therefore, this criterion is not applied at Not Applied strength due to lack of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: 'Domain and hotspot information at E267 is unknown.' Therefore, this criterion is not applied at Not Applied strength because domain significance is not established.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: 'Variant not found in gnomAD or other population databases.' Therefore, this criterion is applied at Moderate strength because it is absent from large population datasets.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders).' The evidence for this variant shows: 'No zygosity or trans data available.' Therefore, this criterion is not applied at Not Applied strength due to lack of trans inheritance data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: 'Protein change is a single amino acid substitution (E267D), no length change.' Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen.' The evidence for this variant shows: 'No other pathogenic missense at position 267 reported.' Therefore, this criterion is not applied at Not Applied strength due to lack of previous pathogenic variants at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: 'No inheritance or de novo data provided.' Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: 'No segregation data provided.' Therefore, this criterion is not applied at Not Applied strength due to absent family segregation information.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: 'RECQL4 disease mechanism is primarily loss of function, not missense.' Therefore, this criterion is not applied at Not Applied strength because missense is not a common pathogenic mechanism for RECQL4.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: 'SpliceAI score 0.05 and other in silico tools indicate no impact.' Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: 'No phenotype or clinical information provided.' Therefore, this criterion is not applied at Not Applied strength due to missing phenotype data.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: 'No entries in ClinVar or other databases.' Therefore, this criterion is not applied at Not Applied strength because no reputable source classifies it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: 'Variant absent in population databases.' Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not above threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: 'Variant absent, frequency not greater than expected.' Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant or fully penetrant disorder.' The evidence for this variant shows: 'No healthy adult data available.' Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: 'No functional assays performed.' Therefore, this criterion is not applied at Not Applied strength due to absence of functional data.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: 'No segregation data.' Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where loss of function is the known mechanism of disease.' The evidence for this variant shows: 'E267D is a missense change in RECQL4, a gene primarily affected by truncating variants.' Therefore, this criterion is applied at Supporting strength because the gene mechanism is LOF and this is a missense.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant.' The evidence for this variant shows: 'No trans or cis data available.' Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in a repetitive region without known function.' The evidence for this variant shows: 'Variant is a single amino acid substitution, not an in-frame indel in a repetitive region.' Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: 'SpliceAI predicts no splicing impact (0.05) and other in silico tools are non-deleterious.' Therefore, this criterion is applied at Supporting strength because computational analyses predict benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: 'No case reports or alternate diagnoses provided.' Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence.' The evidence for this variant shows: 'No external benign classifications available.' Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: 'This is a missense variant, not synonymous.' Therefore, this criterion is not applied at Not Applied strength.