RECQL4 c.3393+9A>G, p.?
NM_004260.4:c.3393+9A>G
COSMIC ID: COSM5020919
Variant of Uncertain Significance (VUS)
The variant NM_004260.4:c.3393+9A>G in RECQL4 is classified as Benign based on stand-alone BA1 evidence from population frequency >5%, strong BS2 evidence from healthy homozygotes, supported by computational benign predictions (BP4) and reputable benign reports (BP6), with no pathogenic evidence identified.
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+9A>G
Protein Change
?
Location
Exon 19
(Exon 19 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5020919
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.3393+9A>G
Active Tracks
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Clinical Data
Global Frequency
2.27%
Common
Highest in Population
Ashkenazi Jewish
7.57%
Common
Global: 2.27%
Ashkenazi Jewish: 7.57%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 277034Alt: 6298Homozygotes: 101
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 2.27%, 6298/277034 alleles, homozygotes = 101) and at a higher frequency in the Ashkenazi Jewish population (MAF= 7.57%, 774/10230 alleles, homozygotes = 32). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Likely Benign
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
1 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (1 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: -0.43
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 or multi-exon deletion)". The evidence for this variant shows: NM_004260.4:c.3393+9A>G is an intronic change outside the canonical ±1 or 2 splice sites and does not create a null allele. Therefore, this criterion is not applied because the variant does not result in a loss-of-function change at a canonical splice site or coding region.
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: it is intronic with no amino acid change and no known pathogenic variant at this position. Therefore, this criterion is not applied because there is no amino acid alteration matching a known pathogenic 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 data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
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+9A>G. Therefore, this criterion is not applied 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 segregation data in affected individuals. Therefore, this criterion is not applied due to lack of case 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: it is intronic and not in a characterized functional domain. Therefore, this criterion is not applied because the variant is outside known critical regions.
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: present in gnomAD with a global MAF of 2.27% and Ashkenazi Jewish MAF of 7.57%. Therefore, this criterion is not applied because the variant is common in the general and subpopulation 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 data on trans configuration with pathogenic variants. Therefore, this criterion is not applied due to lack of segregation/trans 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: it is an intronic substitution with no change to protein length. Therefore, this criterion is not applied because there is no effect on protein length.
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: it is intronic with no amino acid change. Therefore, this criterion is not applied because it does not alter an amino acid 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 de novo data. Therefore, this criterion is not applied due to lack of assumed de novo evidence.
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. Therefore, this criterion is not applied due to absence of familial co-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: it is an intronic change, not a missense variant. Therefore, this criterion is not applied because it is not a missense alteration.
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: SpliceAI score 0.35 (low impact), CADD score -0.43 (benign), mixed computational evidence. Therefore, this criterion is not applied because computational predictions do not consistently support a 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 phenotypic data provided. Therefore, this criterion is not applied due to lack of phenotype information.
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 benign/likely benign, not pathogenic. Therefore, this criterion is not applied because no reputable source reports it as pathogenic.
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: gnomAD global MAF 2.27% and Ashkenazi Jewish MAF 7.57%, exceeding the 5% threshold in a valid population dataset. Therefore, this criterion is applied at Stand Alone strength because the allele frequency is above the BA1 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: although common, BA1 already provides stand-alone benign evidence. Therefore, BS1 is not separately applied to avoid redundancy.
BS2
BS2 (Strong)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: numerous healthy homozygotes in gnomAD (101 globally, 32 Ashkenazi). Therefore, this criterion is applied at Strong strength because the variant is observed in healthy adults.
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 available. Therefore, this criterion is not applied 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 provided. Therefore, this criterion is not applied due to lack of family segregation information.
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: it is intronic, not missense. Therefore, this criterion is not applied because it does not involve a missense change.
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/trans configuration with pathogenic variants. Therefore, this criterion is not applied due to lack of relevant phasing data.
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 substitution in an intronic region. Therefore, this criterion is not applied because it is not an in-frame indel.
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 low impact (0.35) and CADD benign score (-0.43). Therefore, this criterion is applied at Supporting strength because computational tools consistently predict no functional 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 other molecular diagnoses. Therefore, this criterion is not applied due to absence of such case data.
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 submissions from multiple labs classify it as Benign or Likely Benign without detailed evidence. Therefore, this criterion is applied at Supporting strength because reputable sources report the variant as benign.
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 intronic, not synonymous. Therefore, this criterion is not applied because it does not involve a synonymous coding change.