RECQL4 c.801G>C, p.Glu267Asp
NM_004260.4:c.801G>C
COSMIC ID: COSM3763202
Likely Benign
This RECQL4 p.E267D variant is extremely common in population databases (MAF 43.5% with numerous homozygotes), computational evidence predicts no impact, and reputable sources report it as benign. Combined benign criteria (BA1, BS1, BS2, BP1, BP4, BP6) support a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP1
BP4
BP6
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.801G>C
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
Alternate Identifiers
COSM3763202
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.801G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
43.5%
Common
Highest in Population
Admixed American
53.3%
Common
Global: 43.5%
Admixed American: 53.3%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 272154Alt: 118494Homozygotes: 25961
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 43.5%, 118494/272154 alleles, homozygotes = 25961) and at a higher frequency in the Admixed American population (MAF= 53.3%, 18476/34644 alleles, homozygotes = 4953). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
11 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (11 clinical laboratories).
COSMIC ID
COSM3763202
Recurrence
27 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.30
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 (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is a missense variant (c.801G>C; p.E267D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no known pathogenic variant has been reported at amino acid position 267 in RECQL4. Therefore, this criterion is not applied.
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 de novo data are available. Therefore, this criterion is not applied.
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 on RECQL4 p.E267D. Therefore, this criterion is not applied.
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 affected individual data are available. Therefore, this criterion is not applied.
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: E267 is not within a known mutational hotspot or critical functional domain of RECQL4. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
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: MAF=43.5% in gnomAD, far from absent or extremely low. Therefore, this criterion is not applied.
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 data on trans configuration with any pathogenic RECQL4 variant. Therefore, this criterion is not applied.
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: it is a missense substitution with no change in protein length. Therefore, this criterion is not applied.
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 changes have been reported at residue 267 of RECQL4. Therefore, this criterion is not applied.
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 de novo data at all. Therefore, this criterion is not applied.
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 family segregation data. Therefore, this criterion is not applied.
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 missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: RECQL4 disease mechanism is loss-of-function, not missense, and the variant is common in population. Therefore, this criterion is not applied.
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/gene product'. The evidence for this variant shows: in silico predictors (CADD, SpliceAI) indicate no deleterious impact. Therefore, this criterion is not applied.
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 patient phenotype or clinical data are provided. Therefore, this criterion is not applied.
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 reputable source reports this as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: MAF in gnomAD is 43.5% (118,494/272,154 alleles, including 25,961 homozygotes). Therefore, this criterion is applied at Stand Alone strength because the allele frequency far exceeds any threshold compatible with pathogenicity.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF of 43.5% in gnomAD greatly exceeds expected maximum allele frequency for RECQL4-related disease. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Strong)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: 25,961 homozygotes are present in gnomAD, a database of presumably healthy individuals. Therefore, this criterion is applied at Strong 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 studies exist. Therefore, this criterion is not applied.
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 family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease'. The evidence for this variant shows: RECQL4-related conditions are caused by loss-of-function variants, and this is a missense variant. Therefore, this criterion is applied at Supporting strength.
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 data on cis or trans configuration with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: it is a single nucleotide missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
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: CADD score of –0.30 and SpliceAI score of 0.00 indicate no deleterious or splicing impact. Therefore, this criterion is applied at Supporting strength.
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 with an alternate molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
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: ClinVar contains 11 submissions classifying it as Benign without underlying data. Therefore, this criterion is applied at Supporting 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: it is a missense variant, not synonymous. Therefore, this criterion is not applied.