RECQL4 c.3393+8C>T, p.?
NM_004260.4:c.3393+8C>T
COSMIC ID: COSM3765393
Likely Benign
The intronic RECQL4 variant c.3393+8C>T is extremely common in the general population (BA1, BS1, BS2), shows benign computational predictions (BP4), and is reported as benign in ClinVar (BP6), supporting a Benign classification.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
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.3393+8C>T
Protein Change
?
Location
Exon 19
(Exon 19 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM3765393
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.3393+8C>T
Active Tracks
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Clinical Data
Global Frequency
46.5%
Common
Highest in Population
South Asian
56.7%
Common
Global: 46.5%
South Asian: 56.7%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 276276Alt: 128531Homozygotes: 31642
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 46.5%, 128531/276276 alleles, homozygotes = 31642) and at a higher frequency in the South Asian population (MAF= 56.7%, 17334/30558 alleles, homozygotes = 5022). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
9 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (9 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.37
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'. The evidence for this variant shows: c.3393+8C>T is an intronic change outside the canonical ±1 or 2 splice sites and does not introduce a null effect. Therefore, this criterion is not applied 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 known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no amino acid change is predicted for c.3393+8C>T. Therefore, this criterion is not applied because there is no matching 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 de novo data available. Therefore, this criterion is not applied 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 for c.3393+8C>T. Therefore, this criterion is not applied due to absence of functional data.
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 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: the intronic +8 position is not within a known functional 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 for this variant shows: allele frequency is 46.5% in gnomAD, which is far above low frequency. Therefore, this criterion is not applied because the variant is common.
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 a known pathogenic variant. Therefore, this criterion is not applied due to lack of trans configuration 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: c.3393+8C>T does not alter coding sequence or 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 missense change is involved. 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 data on assumed de novo occurrence. 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 due to lack of 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 missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: c.3393+8C>T is noncoding. 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'. The evidence for this variant shows: computational tools indicate no significant impact (CADD 0.37; SpliceAI low). Therefore, this criterion is not applied because evidence suggests benign impact.
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 data 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: ClinVar reports the 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'. The evidence for this variant shows: MAF=46.5% with 31,642 homozygotes in gnomAD. Therefore, this criterion is applied at Stand Alone strength because allele frequency far exceeds any threshold for 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=46.5% in gnomAD. Therefore, this criterion is applied at Strong strength because the variant is far more common than expected for disease.
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: 31,642 homozygotes in gnomAD presumed healthy. Therefore, this criterion is applied at Strong strength because many healthy individuals harbor the variant in homozygosity.
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 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'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: c.3393+8C>T is noncoding. Therefore, this criterion is not applied.
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 information on cis/trans 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: 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'. The evidence for this variant shows: CADD score 0.37 and SpliceAI predicts no significant splicing impact. Therefore, this criterion is applied at Supporting strength because computational data support benign impact.
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 alternate molecular basis. 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 lists it as benign by nine 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'. The evidence for this variant shows: c.3393+8C>T is intronic, not synonymous. Therefore, this criterion is not applied.