RECQL4 c.3014G>A, p.Arg1005Gln
NM_004260.4:c.3014G>A
COSMIC ID: COSM9988414
Likely Benign
This variant is benign based on BA1 stand-alone due to its extremely high allele frequency (45.6%), supported by BS1, BS2, BP1, BP4, and BP6 showing no evidence of pathogenicity.
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.3014G>A
Protein Change
R1005Q
Location
Exon 17
(Exon 17 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1005 in gene RECQL4
Alternate Identifiers
COSM9988414
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.3014G>A
Active Tracks
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Clinical Data
Global Frequency
45.6%
Common
Highest in Population
South Asian
56.3%
Common
Global: 45.6%
South Asian: 56.3%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 274802Alt: 125425Homozygotes: 30362
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 45.6%, 125425/274802 alleles, homozygotes = 30362) and at a higher frequency in the South Asian population (MAF= 56.3%, 17153/30458 alleles, homozygotes = 4925). 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).
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 1005 in gene RECQL4
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.07
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..." The evidence for this variant shows it is a missense change (R1005Q), 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 there is no known pathogenic variant causing the same R1005Q change. 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." No de novo data are available for this variant. 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." Functional studies have not been performed for R1005Q. 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." 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." No data indicate R1005 is in such a domain or hotspot. 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 shows a population MAF of 45.6%, which is not 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)." No data on compound heterozygosity/trans phase are available. 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." This is a missense variant with no length change. 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." There is no known pathogenic missense at R1005. 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." No de novo assumption data are available. 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." No segregation data are available. 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." RECQL4 disease mechanism is primarily loss of function, not missense. 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 computational evidence (CADD=1.07; SpliceAI=0.01) supports no deleterious effect. 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." No phenotype or family history 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." ClinVar reports this variant as benign, not 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 a MAF of 45.6% in gnomAD, far exceeding disease prevalence thresholds. Therefore, this criterion is applied at Stand Alone strength.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence shows MAF=45.6%, which is well above expectations for pathogenic variants in RECQL4. 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 shows 30,362 homozygotes in gnomAD with no reported disease. 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." No functional studies have been conducted. 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." No segregation data are available. 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." RECQL4 disease is due to loss-of-function variants, and this is a missense change. 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." No phase data are available. 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." This is 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." Computational tools (CADD=1.07; SpliceAI=0.01) predict no 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." No such case data are available. 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." ClinVar records this variant as benign from 11 laboratories. 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." This variant is missense, not synonymous. Therefore, this criterion is not applied.