SETBP1 c.3364A>T, p.Ser1122Cys
NM_015559.2:c.3364A>T
Population Frequency
0.000398%
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.083
Likely Benign
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
SETBP1
Transcript
NM_015559.3
MANE Select
Total Exons
6
Strand
Forward (+)
Reference Sequence
NC_000018.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_015559.1 | Alternative | 5 exons | Forward |
| NM_015559.2 | Alternative | 6 exons | Forward |
Variant Details
HGVS Notation
NM_015559.2:c.3364A>T
Protein Change
S1122C
Location
Exon 4
(Exon 4 of 6)
5'
Exon Structure (6 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1122 in gene SETBP1
Variant interpretation based on transcript NM_015559.3
Clinical Evidence
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.00088%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.00088%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251298
Alt: 1
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251298 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00088%, 1/113598 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
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 1122 in gene SETBP1
Functional Studies
Summary
The SETBP1 S1122C variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.083
0.083
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.34
polyphen_prediction: benign
metasvm: T
metalr: T
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PVS1 – 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 it is a missense change (S1122C) and does not result in a null effect. Therefore, this criterion is not applied at Not Applied strength.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PS1 – Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant does not report any previously established pathogenic variant with the same amino acid change. Therefore, this criterion is not applied at Not Applied strength.
PS2
PS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. There is no de novo occurrence or confirmation provided for this variant. Therefore, this criterion is not applied at Not Applied strength.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines, the finding for PS3 is: 'The SETBP1 S1122C variant has not been functionally characterized, and its biological significance remains unknown'. The evidence does not support a damaging effect on the protein. Therefore, this criterion is not applied at Not Applied strength.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. There is no evidence that the prevalence of this variant is increased in affected individuals relative to controls. Therefore, this criterion is not applied at Not Applied strength.
PM1
PM1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant does not indicate localization in a known mutational hot spot or critical domain. Therefore, this criterion is not applied at Not Applied strength.
PM2
PM2 (Moderate)
According to Standard ACMG guidelines, 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows an extremely low minor allele frequency (MAF = 0.000398%) in gnomAD and other population databases. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. There is no evidence provided for this variant being observed in trans with any pathogenic variant. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant does not indicate a protein length change, as it is a missense change. Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant does not report another pathogenic missense change at residue S1122. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. There is no information supporting a de novo occurrence for this variant. Therefore, this criterion is not applied at Not Applied strength.
PP1
PP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PP1 – Co-segregation with disease in multiple affected family members'. There is no segregation data available for this variant. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. Although SETBP1 can be associated with missense variants, there is no additional evidence suggesting this variant is deleterious. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The in silico evidence for this variant (e.g., REVEL score of 0.08 and SpliceAI max score of 0.01) supports a benign impact rather than a deleterious one. Therefore, this criterion is not applied at Not Applied strength.
PP4
PP4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PP4 – Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. There is no provided phenotype or family history information specific enough to apply this criterion. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. Although ClinVar lists this variant as VUS by several laboratories, it does not reach the threshold for a pathogenic report with accessible evidence. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BA1 – Allele frequency is too high for the disorder'. The allele frequency for this variant is extremely low (MAF = 0.000398%), which does not meet the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BS1 – Allele frequency is greater than expected for disorder'. The evidence indicates that the variant is very rare, hence BS1 is not met. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BS2 – Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. There is no evidence provided that this variant is observed in healthy individuals in a manner that supports BS2. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing'. No functional studies have been performed that definitively show the absence of a damaging effect for this variant. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BS4 – Lack of segregation in affected family members'. There is no segregation data available for this variant. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP1 – Missense variant in a gene for which primarily truncating variants are known to cause disease'. The spectrum of pathogenic variants in SETBP1 is not exclusively truncating; thus, BP1 is not applicable. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. There is no evidence indicating that this variant is observed in trans or in cis with any pathogenic variant. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant, being a missense change, does not involve in-frame insertions or deletions. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to Standard ACMG guidelines, 'BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. The evidence for this variant includes a REVEL score of 0.08 and a SpliceAI max score of 0.01, both of which support a benign interpretation. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP5 – Variant found in a case with an alternate molecular basis for disease'. There is no evidence indicating an alternative molecular cause in this case. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. Despite ClinVar entries listing this variant as VUS, the evidence is not sufficient to apply BP6. Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, 'BP7 – Synonymous variant with no predicted impact on splicing'. Since the variant results in an amino acid change (S1122C) and is not synonymous, this criterion is not applicable. Therefore, this criterion is not applied at Not Applied strength.