About SETBP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SETBP1 c.2953A>G, p.(Ile985Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 1.41×10⁻⁵ (4/282,746 alleles, 0 homozygotes), gnomAD v4.1 allele frequency 3.97×10⁻⁵ (64/1,613,756 alleles, 0 homozygotes), with grpmax filtering allele frequency of 3.94×10⁻⁵. All frequencies are well below the 0.1% threshold for PM2 in non-VCEP generic ACMG/AMP application.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
64 / 1,613,756 alleles
gnomAD v4.1: 64 / 1,613,756 alleles. Recorded AF 3.9659e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4147e-05; MAF= 0.00141%, 4/282746 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138427; MAF= 0.01384%, 1/7224 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Uncertain significance · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 4 not met · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_015559.2:c.2953A>G (p.Ile985Val) in SETBP1 is absent from or extremely rare in large population cohorts (gnomAD v4.1 AF = 3.97×10⁻⁵), meeting PM2 at a supporting level.
This is a missense variant; PVS1 is not applicable because it does not fall into null-variant categories. In silico predictions are mixed: REVEL is intermediate (0.591), BayesDel is benign (0.050), and SpliceAI predicts no splicing impact (delta = 0.00), so neither PP3 nor BP4 is met.
No functional studies, segregation data, de novo observations, case-control evidence, or authoritative pathogenic/benign classifications are available for this specific variant.
With only one supporting-level pathogenic criterion (PM2_Supporting) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance under generic ACMG/AMP 2015 rules.
No criteria match.
Met · 1
PM2 SupportingThis variant is extremely rare in population databases: gnomAD v2.1 allele frequency 1.41×10⁻⁵ (4/282,746 alleles, 0 homozygotes), gnomAD v4.1 allele frequency 3.97×10⁻⁵ (64/1,613,756 alleles, 0 homozygotes), with grpmax filtering allele frequency of 3.94×10⁻⁵. All frequencies are well below the 0.1% threshold for PM2 in non-VCEP generic ACMG/AMP application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=1.41e-05
- 4/282
- 746 alleles
- 0 homozygotes
- grpmax FAF=2.92e-06
- gnomAD v4.1: AF=3.97e-05
- 64/1
- 613
- 756 alleles
- grpmax FAF=3.94e-05
- gnomAD-Canada: not available
Sources
Not met · 4 · evaluated, threshold not reached
PP3 In silico predictions are mixed and do not converge on a deleterious effect: REVEL score 0.591 is in an intermediate range below typical pathogenic thresholds, BayesDel score 0.050 is strongly benign, and SpliceAI max delta is 0.00. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.591 (intermediate
- not strongly pathogenic)
- BayesDel: 0.050 (benign prediction)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BA1 The allele frequency is far below the 1% BA1 threshold: gnomAD v4.1 total AF = 3.97×10⁻⁵ (0.004%). This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 3.97e-05 (0.004%)
- well below 1% BA1 threshold
Sources
BS1 The allele frequency is below the 0.3% BS1 threshold: gnomAD v4.1 maximum subpopulation AF = 8.0×10⁻⁵ (0.008%) in Remaining individuals. This variant is not present at a frequency expected for a standing benign variant. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF = 8.00e-05 (0.008%)
- well below 0.3% BS1 threshold
Sources
BP4 In silico predictions are mixed and do not consistently support no impact on the gene product. While BayesDel (0.050) and SpliceAI (0.00) predict a benign or neutral effect, REVEL (0.591) is in an intermediate range and does not clearly predict a benign effect. Multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.591 (intermediate
- not clearly benign)
- BayesDel: 0.050 (benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
Not assessed · 17 · no assessment recorded
PS1 No evidence of a different nucleotide change at the same amino acid position (Ile985) with established pathogenicity was identified in the case evidence. Details ▾Hide ▴
Still missing
- No same-residue pathogenic comparator variant identified in ClinVar
- literature
- or case materials.
PS2 No de novo data were available for this variant in the case evidence; PS2 requires confirmed de novo occurrence with parental testing. Details ▾Hide ▴
Still missing
- No de novo testing data provided for this case.
PS3 No functional studies were identified for NM_015559.2:c.2953A>G (p.Ile985Val). OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence; literature pass identified no functional studies for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence found.
Still missing
- No in vitro or in vivo functional data available for this specific missense variant.
Sources
PS4 No case-control studies or statistical evidence for enrichment of this variant in affected individuals versus controls was identified. Details ▾Hide ▴
Still missing
- No case-control or cohort enrichment data available.
PM1 The variant does not lie in a statistically significant mutational hotspot and no evidence places residue 985 within a critical functional domain devoid of benign variation. Details ▾Hide ▴
Evidence considered
- Hotspot analysis negative
- residue 985 is not in a statistically significant hotspot.
Still missing
- No domain-level constraint data or functional domain annotation for residue 985.
PM6 No de novo data were available for this variant; PM6 requires confirmed de novo occurrence without parental testing confirmation. Details ▾Hide ▴
Still missing
- No de novo testing data provided.
PP1 No segregation data were available for this variant; PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data provided.
PP2 Missense constraint metrics (e.g., Z-score) for SETBP1 were not available in the case evidence; PP2 requires demonstration of a low rate of benign missense variation in the gene. Details ▾Hide ▴
Still missing
- No missense constraint Z-score or intolerance metric for SETBP1 available.
PP4 No phenotype specificity data were available; PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype or family history data provided.
PP5 No reputable source has classified this variant as pathogenic. ClinVar submissions are conflicting (VUS and Benign) and neither represents an expert panel or multi-submitter consensus. No literature source definitively reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: conflicting VUS (1 lab) and Benign (1 lab)
- insufficient for PP5.
Still missing
- No authoritative pathogenic classification from a reputable source.
Sources
BS2 No data on observation of this variant in healthy adults were available for a disorder expected to be fully penetrant at an early age. Details ▾Hide ▴
Still missing
- No data on healthy adult carriers for a fully penetrant early-onset disorder.
BS3 No functional studies demonstrating no damaging effect on protein function or splicing were identified for this specific variant. Details ▾Hide ▴
Still missing
- No well-established in vitro or in vivo functional studies showing no deleterious effect.
BS4 No segregation data demonstrating lack of cosegregation with disease were available. Details ▾Hide ▴
Still missing
- No family segregation data to evaluate lack of cosegregation.
BP2 No data on observation of this variant in trans with a known pathogenic variant in a recessive disorder were available. Details ▾Hide ▴
Still missing
- No data on co-occurrence in trans with a pathogenic variant.
BP5 No alternate molecular basis for disease was identified in this case; BP5 requires a plausible alternate cause for the observed phenotype. Details ▾Hide ▴
Still missing
- No data on alternate molecular findings in this individual.
BP6 ClinVar contains one benign submission (Labcorp/Invitae, single submitter) and one VUS submission (Ambry Genetics). A single-submitter benign classification does not meet the BP6 threshold of a reputable source reporting the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: one benign submission (Labcorp/Invitae
- single submitter) does not satisfy BP6 reputable-source requirement.
Still missing
- No multi-submitter or expert panel benign classification.
Sources
PS5 No reputable source has classified this variant as definitively pathogenic. ClinVar shows conflicting interpretations of Uncertain Significance and Benign, each from single submitters without expert panel review. Details ▾Hide ▴
Evidence considered
- ClinVar VUS (Ambry Genetics) and Benign (Labcorp/Invitae)
- both single submitters
- no expert panel classification.
Still missing
- No authoritative pathogenic classification from a reputable source.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (NP_056374.2:p.Ile985Val) that does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable per ClinGen SVI PVS1 decision tree. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/AUnable to confirm classic same-residue PM5 semantics; no comparator missense variants at residue Ile985 were identified via candidate harvesting. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue comparators.
Sources
pm5_candidates
BP1 N/ASETBP1 is associated with both loss-of-function (SETBP1 haploinsufficiency disorder) and gain-of-function missense (Schinzel-Giedion syndrome) germline disease mechanisms. The gene has well-established pathogenic missense variants and is not one for which 'primarily truncating variants are known to cause disease.' BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- SETBP1 has dual mechanisms: LoF (SETBP1-HD) and GoF missense (SGS)
- pathogenic missense variants are well-established.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.2953A>G, p.Ile985Val) and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Identifiers
- Gene
- SETBP1
- Transcript
- NM_015559.2
- Coding (HGVS c.)
- NM_015559.2:c.2953A>G
- Protein (HGVS p.)
- NP_056374.2:p.(Ile985Val)
- GRCh38
- chr18:44952293 A>G
- GRCh37
- chr18:42532258 A>G
- ClinVar
- 1474529
Gene diagram
Every interpreted variant in SETBP1, mapped onto the exon structure of NM_015559.2. Select a row to find it on the plot.
SETBP1NM_015559.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SETBP1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
64 / 1,613,756 alleles
AF 3.97e-05 · 0 homozygotes · FAF 3.94e-05
gnomAD v2.1
4 / 282,746 alleles
AF 1.41e-05 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4e-05 · 64 / 1,613,756 alleles · 0 hom · FAF 3.9e-05
| Remaining individuals5 / 62,484 | 8e-05 |
| European (non-Finnish)59 / 1,179,978 | 5e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,746 alleles · 0 hom · FAF 2.9e-06
| Remaining individuals1 / 7,224 | 0.00014 |
| European (non-Finnish)3 / 129,080 | 2.3e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.9659e-05; MAF= 0.00397%, 64/1613756 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00205e-05; MAF= 0.00800%, 5/62484 alleles, homozygotes = 0); grpmax FAF= 3.937e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4147e-05; MAF= 0.00141%, 4/282746 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138427; MAF= 0.01384%, 1/7224 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.591
- BayesDel
- 0.050
How the predictions were used
PP3 In silico predictions are mixed and do not converge on a deleterious effect: REVEL score 0.591 is in an intermediate range below typical pathogenic thresholds, BayesDel score 0.050 is strongly benign, and SpliceAI max delta is 0.00. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.591 (intermediate
- not strongly pathogenic)
- BayesDel: 0.050 (benign prediction)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP4 In silico predictions are mixed and do not consistently support no impact on the gene product. While BayesDel (0.050) and SpliceAI (0.00) predict a benign or neutral effect, REVEL (0.591) is in an intermediate range and does not clearly predict a benign effect. Multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.591 (intermediate
- not clearly benign)
- BayesDel: 0.050 (benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This is a missense variant (c.2953A>G, p.Ile985Val) and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.591. BayesDel score = 0.0498507.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015This statement paper discusses the role of whole-genome sequencing in newborn screening programmes and the continued importance of targeted approaches. It does not discuss SETBP1 or any specific genetic variant.Does not name this variant
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PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014This workshop report evaluates the appropriateness of newborn screening for alpha-1 antitrypsin deficiency. It does not discuss SETBP1 or any SETBP1 variant.Does not name this variant
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PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013This paper provides recommendations on including newborn screening bloodspot collection device serial numbers on birth certificates. It is a policy paper and does not discuss SETBP1 or any genetic variants.Does not name this variant
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Botkin JR et al. · 2014This paper provides guidelines for parental permission in pilot newborn screening research. It is an ethics and policy paper and does not discuss SETBP1 or any genetic variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.This paper describes the Sherloc refinement of ACMG-AMP variant classification criteria. It is a methodological framework paper and does not discuss SETBP1 or the specific variant NM_015559.2:c.2953A>G.Does not name this variant
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PMID 31022120 ↗ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.This is an ACOG Committee Opinion on newborn screening and the role of the obstetrician-gynecologist. It is a clinical guidance document and does not discuss SETBP1 or any genetic variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
64 / 1,613,756 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance · 1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1474529/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-42532258-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-44952293-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/18-44952293-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015559.2%3Ac.2953…
- OncoKB ↗www.oncokb.org/gene/SETBP1/I985V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SETBP1+c.2953A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.9659e-05; MAF= 0.00397%, 64/1613756 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00205e-05; MAF= 0.00800%, 5/62484 alleles, homozygotes = 0); grpmax FAF= 3.937e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4147e-05; MAF= 0.00141%, 4/282746 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138427; MAF= 0.01384%, 1/7224 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 1474529)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.591. BayesDel score = 0.0498507.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SETBP1, an epigenetic remodeling protein, is frequently altered by mutation in a range of hematopoietic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.