SETBP1 c.3834G>C, p.Leu1278=
NM_015559.2:c.3834G>C
Likely Benign
The SETBP1 c.3834G>C (p.L1278=) variant is a synonymous change with no predicted impact on splicing or protein function, observed at extremely low allele frequency, supported by benign computational predictions and ClinVar reports. Combined evidence (PM2, BP4, BP6, BP7) supports a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.3834G>C
Protein Change
L1278=
Location
Exon 4
(Exon 4 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_015559.3
Genome Browser
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HGVS InputNM_015559:c.3834G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0206%
Low Frequency
Highest in Population
South Asian
0.134%
Common
Global: 0.0206%
South Asian: 0.134%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281564Alt: 58Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0206%, 58/281564 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.134%, 41/30608 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 LB
2 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (2 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: 0.96
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 (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: NM_015559.2:c.3834G>C is a synonymous change with no predicted impact on protein coding. Therefore, this criterion is not applied because synonymous variants do not result in loss‐of‐function null alleles.
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: p.L1278= is a synonymous change with no amino acid alteration. Therefore, this criterion is not applied because there is no amino acid change to compare to known pathogenic variants.
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 inheritance data are available. Therefore, this criterion is not applied due to absence 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. Therefore, this criterion is not applied because there is no functional data indicating a damaging effect.
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 data demonstrating enrichment 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: c.3834G>C (p.L1278=) is a synonymous change outside known functional domains. Therefore, this criterion is not applied because it is not in a mutational hotspot or critical domain.
PM2
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: gnomAD MAF=0.0206% (58/281,564 alleles) with no homozygotes, extremely rare in population databases. Therefore, this criterion is applied at Moderate strength because the variant is present at an extremely low frequency consistent with PM2.
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 regarding trans configuration with a pathogenic variant. Therefore, this criterion is not applied due to absence of such evidence.
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.3834G>C is a synonymous substitution without protein length change. 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: p.L1278= is synonymous, not a missense change. 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 de novo or family data available. 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 segregation data available. Therefore, this criterion is not applied.
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.3834G>C is synonymous, not a missense variant. 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 on the gene/gene product". The evidence for this variant shows: CADD score 0.96, SpliceAI scores 0, and other in silico tools predict no impact. Therefore, this criterion is not applied because computational evidence supports benign impact, not deleterious.
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.
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 it as benign or likely benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) 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=0.0206%, which is below thresholds for BA1. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
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=0.0206% is not greater than expected for SETBP1-associated disorders. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
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 specific data demonstrating presence in healthy individuals with expected full penetrance. Therefore, this criterion is not applied.
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 performed. 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 family 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.3834G>C is synonymous, not missense. 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 phasing data. 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 indel but a single nucleotide change. 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 0.96, SpliceAI=0, and other predictors concordant with no impact. Therefore, this criterion is applied at Supporting strength because computational evidence predicts no functional or splicing 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.
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 by two laboratories classify it as Benign and one as Likely Benign without detailed evidence available. Therefore, this criterion is applied at Supporting strength because a reputable database reports benign classification.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: p.L1278= is synonymous and SpliceAI predicts no splicing impact (all scores 0). Therefore, this criterion is applied at Supporting strength because it is a silent change with no splicing effect.