Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_015559.1 | Alternative | 5744 nt | 6–4634 |
| NM_015559.2 | Alternative | 9899 nt | 297–5087 |
| NM_015559.3 | MANE Select | 9909 nt | 307–5097 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -50 bp |
| Donor Loss (DL) | 0.0 | -169 bp |
| Acceptor Gain (AG) | 0.0 | 4 bp |
| Donor Gain (DG) | 0.0 | 422 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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 (c.3577G>A; p.A1193T), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
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 at codon 1193 in SETBP1. Therefore, this criterion is not applied.
PS2 (Not Applied)
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 parental testing or de novo status. Therefore, this criterion is not applied.
PS3 (Not Applied)
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.
PS4 (Not Applied)
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. Therefore, this criterion is not applied.
PM1 (Not Applied)
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: residue A1193 is not known to lie within a mutational hotspot or critical domain of SETBP1. Therefore, this criterion is not applied.
PM2 (Moderate)
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=0.00677% in gnomAD (17/251096 alleles), with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
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 compound heterozygosity in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
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 change without alteration of protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
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 variants reported at codon 1193. Therefore, this criterion is not applied.
PM6 (Not Applied)
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.
PP1 (Not Applied)
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 (Not Applied)
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: SETBP1 has both LoF- and missense-mediated disease mechanisms; missense constraint is not uniquely low. Therefore, this criterion is not applied.
PP3 (Not Applied)
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: computational tools predict benign impact (REVEL=0.04, CADD/PolyPhen benign, SpliceAI=0.01). Therefore, this criterion is not applied.
PP4 (Not Applied)
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 data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
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 pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
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=0.00677% which is well below any BA1 threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
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 is low and not greater than disease prevalence thresholds. Therefore, this criterion is not applied.
BS2 (Not Applied)
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: no phenotype-confirmed healthy carriers are documented. Therefore, this criterion is not applied.
BS3 (Not Applied)
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.
BS4 (Not Applied)
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 (Not Applied)
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: SETBP1 has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
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 phase with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
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 change, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene/gene product.' The evidence for this variant shows: REVEL score 0.04 (below 0.15), CADD and PolyPhen benign predictions, SpliceAI max score 0.01. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict benign impact.
BP5 (Not Applied)
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 such case report. Therefore, this criterion is not applied.
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 entry as Likely benign by one clinical laboratory without detailed evidence. Therefore, this criterion is applied at Supporting strength because a reputable source reports benign.
BP7 (Not Applied)
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.