RECQL4 c.1258+18G>A, p.?
NM_004260.4:c.1258+18G>A
COSMIC ID: COSN32290096
Variant of Uncertain Significance (VUS)
The variant c.1258+18G>A in RECQL4 is extremely common in population databases (MAF 46.6%, thousands of homozygotes), meeting BA1 (Stand-alone) and BS1 (Strong). Computational evidence (BP4) predicts no functional impact. No pathogenic evidence is present. Therefore, the variant is classified as Benign.
ACMG/AMP Criteria Applied
BA1
BS1
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.1258+18G>A
Protein Change
?
Location
Exon 6
(Exon 6 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN32290096
Variant interpretation based on transcript NM_004260.4
Genome Browser
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HGVS InputNM_004260:c.1258+18G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
46.6%
Common
Highest in Population
South Asian
56.6%
Common
Global: 46.6%
South Asian: 56.6%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 274914Alt: 128015Homozygotes: 31168
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 46.6%, 128015/274914 alleles, homozygotes = 31168) and at a higher frequency in the South Asian population (MAF= 56.6%, 17073/30170 alleles, homozygotes = 4915). The variant is common (MAF > 1%), supporting BA1 criterion application.
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
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 (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: 'c.1258+18G>A is an intronic change outside the canonical ±1 or 2 splice sites and does not introduce a premature stop codon or frameshift'. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the null variant definition.
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 amino acid change is produced or characterized for this intronic variant'. Therefore, this criterion is not applied at Not Applied strength because there is no matching 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 de novo segregation or familial data are available'. Therefore, this criterion is not applied at Not Applied strength 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'. Therefore, this criterion is not applied at Not Applied strength because no functional data are available.
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 patient prevalence data are available'. Therefore, this criterion is not applied at Not Applied strength due to absence of case-control evidence.
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: 'Intronic location outside known functional domains'. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a mutational hot spot or functional domain.
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) in population databases'. The evidence for this variant shows: 'MAF = 46.6% in gnomAD, including 31168 homozygotes'. Therefore, this criterion is not applied at Not Applied strength because the variant is common in controls.
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 compound heterozygote data are available'. Therefore, this criterion is not applied at Not Applied strength due to lack of trans-occurrence 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: 'No effect on protein coding sequence'. Therefore, this criterion is not applied at Not Applied strength because there is no change to 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: 'Intronic location with no amino acid change'. Therefore, this criterion is not applied at Not Applied strength.
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 are available'. Therefore, this criterion is not applied at Not Applied strength.
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 available'. Therefore, this criterion is not applied at Not Applied strength.
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 where missense is a common mechanism'. The evidence for this variant shows: 'Variant is intronic'. Therefore, this criterion is not applied at Not Applied strength.
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: 'In silico tools and SpliceAI predict 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 family history data provided'. Therefore, this criterion is not applied at Not Applied strength.
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: 'Not reported in ClinVar or other reputable sources'. Therefore, this criterion is not applied at Not Applied strength.
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 = 46.6% in gnomAD with 31168 homozygotes'. Therefore, this criterion is applied at Stand-alone strength because the allele frequency exceeds 5%.
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 = 46.6% in gnomAD, well above any expected threshold for disease'. Therefore, this criterion is applied at Strong strength because the allele frequency is greater than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual with full penetrance expected at an early age'. The evidence for this variant shows: 'Homozygotes in population databases but RECQL4-related disorders are recessive and carriers are expected to be healthy'. Therefore, this criterion is not applied at Not Applied strength because carrier status in recessive disease does not meet BS2.
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 at Not Applied strength.
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 available'. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied) Strength Modified
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: 'Intronic change, not missense'. Therefore, this criterion is not applied at Not Applied 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 a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: 'No phasing or compound 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 deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: 'Variant is a single nucleotide change in intron'. 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 impact on splicing; other in silico tools predict benign effect'. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a deleterious 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 with alternate molecular findings'. 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: 'Not reported in ClinVar or other reputable sources'. 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: 'Intronic change, not synonymous coding'. Therefore, this criterion is not applied at Not Applied strength.