About PIK3R1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3R1 c.1011T>G, p.(Asp337Glu)
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 ClinGen PIK3R1 VCEP v1.0.0. 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
NM_181523.2:c.1011T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The total allele frequency of 0.0 is below the VCEP PM2_Supporting threshold of <0.00000132 (derived from the Whiffin/Ware calculator using autosomal dominant parameters: prevalence 1/4000, penetrance 0.95).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0.0 v1.0.0 point-based framework: PM2 supporting (+1) = 1 points, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers.
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 ClinGen PIK3R1 VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 14 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_181523.2:c.1011T>G (p.Asp337Glu) is a missense variant in exon 8 of PIK3R1. It is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold for rarity (PM2_Supporting).
REVEL score is 0.333, which falls between the VCEP thresholds for PP3 (>= 0.644) and BP4 (<= 0.290); neither in silico criterion is met. SpliceAI predicts no splicing impact (max delta 0.02).
No functional studies have tested this variant in any VCEP-approved assay. The variant is absent from ClinVar with no prior classifications. No publications, case reports, or segregation data exist for this variant.
Under the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP, the only met criterion is PM2_Supporting (+1 point), yielding a total score of +1, which falls in the Uncertain Significance range (0-5 points).
No criteria match.
Met · 1
PM2 SupportingNM_181523.2:c.1011T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The total allele frequency of 0.0 is below the VCEP PM2_Supporting threshold of <0.00000132 (derived from the Whiffin/Ware calculator using autosomal dominant parameters: prevalence 1/4000, penetrance 0.95). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- Absent from gnomAD v4.1 (0 alleles).
- Absent from gnomAD-Canada v1.0.
Sources
Not met · 14 · evaluated, threshold not reached
PVS1 NM_181523.2:c.1011T>G is a missense variant (p.Asp337Glu). The ClinGen Antibody Deficiencies VCEP PVS1 rules apply only to nonsense, frameshift, and canonical splice variants; missense variants are not eligible for PVS1 under this framework. Details ▾Hide ▴
Evidence considered
- Missense variant not eligible for PVS1 under VCEP rules
- VCEP PVS1 criteria are limited to null variants (nonsense
- frameshift
- canonical splice).
Sources
cspec ↗pvs1_variant_assessment
PS1 No other nucleotide change encoding the same amino acid (p.Asp337Glu) has been classified as Pathogenic or Likely Pathogenic by the Antibody Deficiencies VCEP. This variant is absent from ClinVar and no prior classification exists for this residue change. Details ▾Hide ▴
PS2 No de novo occurrence data are available for NM_181523.2:c.1011T>G. No proband has been reported with confirmed maternity and paternity harboring this variant. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified in any source for this variant.
Still missing
- No proband data available
- de novo status cannot be assessed.
PS3 No functional studies have been performed on NM_181523.2:c.1011T>G (p.Asp337Glu). The VCEP-approved functional assays (AKT kinase activity, lipid kinase activity, protein binding, conformational dynamics, and the pAKT/pS6 enrichment assay from PMID:40543502) have not tested this variant. Of note, the related synonymous variant p.Asp337Asp was tested in the PMID:40543502 screen but not p.Asp337Glu. Details ▾Hide ▴
Evidence considered
- Variant not tested in any VCEP-approved in vitro functional assay
- p.Asp337Asp was included in PMID:40543502 screen but p.Asp337Glu was not.
Still missing
- No functional data exist for this variant
- PS3 cannot be applied without variant-specific experimental evidence.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4 No probands harboring NM_181523.2:c.1011T>G have been reported. The variant is absent from ClinVar, and no case reports or cohort studies have documented affected individuals with this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no probands identified in any source.
Still missing
- No proband or case data available.
Sources
PP1 No co-segregation data are available for NM_181523.2:c.1011T>G. No family studies or segregation analyses have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation or family data identified.
Still missing
- No family studies available.
PP3 The VCEP PP3 requires REVEL >= 0.644 AND CADD >= 26.0, OR a SpliceAI delta score >= 0.2. REVEL for this variant is 0.333 (below threshold), SpliceAI max delta is 0.02 (below threshold), and CADD is not available but both required conditions are not met independently. Details ▾Hide ▴
Evidence considered
- REVEL score 0.333 (threshold >= 0.644 not met).
- SpliceAI max delta 0.02 (threshold >= 0.2 not met).
Still missing
- CADD score not available but not needed for determination given REVEL and SpliceAI both below thresholds.
Sources
PP4 No proband clinical data are available for NM_181523.2:c.1011T>G. PP4 requires a proband scoring >=10 phenotype points on the PS4 counting rubric with genotyping ruling out PIK3CD variants, and no such proband has been reported. Details ▾Hide ▴
Evidence considered
- No proband with phenotype data identified.
Still missing
- No proband clinical data available.
BA1 NM_181523.2:c.1011T>G is absent from gnomAD v4.1.0 (allele frequency 0.0). The VCEP BA1 threshold requires GrpMax filtering allele frequency >= 0.00316, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0.0)
- does not meet BA1 threshold of >= 0.00316.
Sources
BS1 NM_181523.2:c.1011T>G is absent from gnomAD v4.1.0 (allele frequency 0.0). The VCEP BS1 threshold requires GrpMax filtering allele frequency >= 0.000316, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0.0)
- does not meet BS1 threshold of >= 0.000316.
Sources
BS3 No functional studies showing a non-damaging effect have been performed on NM_181523.2:c.1011T>G. The variant has not been tested in any VCEP-approved in vitro assay. BS3 cannot be applied without variant-specific experimental evidence of normal function. Details ▾Hide ▴
Evidence considered
- Variant not tested in any VCEP-approved functional assay
- no evidence of normal function available.
Still missing
- No functional data exist for this variant.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4 No segregation data are available for NM_181523.2:c.1011T>G. BS4 requires at least one affected family member lacking the variant (with >=6 PS4 phenotype points), and no such data exist. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family studies available.
BP4 The VCEP BP4 requires REVEL <= 0.290 AND CADD <= 21.5 AND all SpliceAI delta scores < 0.1. REVEL for this variant is 0.333 (above the 0.290 threshold), so BP4 is not met. While all SpliceAI delta scores are < 0.1, the REVEL score exceeds the benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL score 0.333 exceeds BP4 threshold of <= 0.290.
- SpliceAI max delta 0.02 (all deltas < 0.1).
Still missing
- CADD score not available but REVEL alone fails the BP4 threshold.
Sources
BP5 No cases have been reported in which NM_181523.2:c.1011T>G was found in a patient with an alternative molecular basis for disease. The VCEP requires at least 2 such cases for BP5_Supporting. Details ▾Hide ▴
Evidence considered
- No evidence of this variant occurring in cases with alternative molecular diagnoses.
Still missing
- No case-level data available.
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 VCEPPM1 is designated as Not Applicable by the ClinGen Antibody Deficiencies VCEP for PIK3R1. Additionally, this variant does not lie in a statistically significant mutational hotspot. Details ▾Hide ▴
Evidence considered
- VCEP marks PM1 as not applicable
- no significant hotspot identified for this residue.
Sources
PM3 VCEPPM3 is specific to recessive disorders; PIK3R1-related immunodeficiency is autosomal dominant. Details ▾Hide ▴
Sources
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. NM_181523.2:c.1011T>G is a missense substitution. Details ▾Hide ▴
Sources
PM5 N/APer the ClinGen Antibody Deficiencies VCEP instructions for PM5: 'Do not apply to missense variants given that missense variation is not a well-described contributor to PIK3R1-related APDS.' NM_181523.2:c.1011T>G is a missense variant and is therefore excluded from PM5 under VCEP rules. Details ▾Hide ▴
Evidence considered
- VCEP PM5 instructions explicitly exclude missense variants from this criterion.
Sources
PM6 VCEPThe ClinGen Antibody Deficiencies VCEP designates PM6 as Not Applicable, instructing that PS2 should be used in lieu of PM6 for apparent de novo occurrences. Details ▾Hide ▴
Evidence considered
- VCEP marks PM6 as not applicable
- PS2 used for de novo assessment instead.
Sources
PP2 VCEPThe ClinGen Antibody Deficiencies VCEP designates PP2 as Not Applicable for PIK3R1. The gnomAD v2.1.1 missense Z score for PIK3R1 (Z = 2.72) indicates this gene is not constrained for missense variation. Details ▾Hide ▴
Evidence considered
- VCEP marks PP2 as not applicable
- gnomAD missense Z = 2.72 does not support constraint.
Sources
PP5 VCEPThe ClinGen Antibody Deficiencies VCEP designates PP5 as Not Applicable for this VCEP, per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS2 VCEPThe ClinGen Antibody Deficiencies VCEP designates BS2 as Not Applicable for PIK3R1 due to incomplete penetrance and variable expressivity of disease. Details ▾Hide ▴
Evidence considered
- VCEP marks BS2 as not applicable due to incomplete penetrance and variable expressivity.
Sources
BP1 VCEPThe ClinGen Antibody Deficiencies VCEP designates BP1 as Not Applicable because pathogenic PIK3R1 variants are not limited to truncating variants but include missense variants as well. Details ▾Hide ▴
Evidence considered
- VCEP marks BP1 as not applicable
- pathogenic PIK3R1 variants include missense changes.
Sources
BP2 VCEPThe ClinGen Antibody Deficiencies VCEP designates BP2 as Not Applicable because the full spectrum of allelic mechanisms for PIK3R1 is not yet understood, and diverse combinatorial variant effects cannot be excluded. Details ▾Hide ▴
Evidence considered
- VCEP marks BP2 as not applicable due to incomplete understanding of PIK3R1 allelic mechanisms.
Sources
BP3 VCEPBP3 is designated Not Applicable by the VCEP because repetitive regions of unknown function are not known within PIK3R1. Details ▾Hide ▴
Sources
BP6 VCEPThe ClinGen Antibody Deficiencies VCEP designates BP6 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous or intronic variants not predicted to impact splicing. NM_181523.2:c.1011T>G is a missense variant (p.Asp337Glu) and is not eligible for BP7 under VCEP rules. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is limited to synonymous and intronic variants per VCEP specification.
Sources
PS5 N/APS5 is not defined in the ClinGen Antibody Deficiencies VCEP specifications for PIK3R1 (version 1.0.0). Under the governing VCEP framework, this criterion is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- PIK3R1
- Transcript
- NM_181523.2
- Coding (HGVS c.)
- NM_181523.2:c.1011T>G
- Protein (HGVS p.)
- NP_852664.1:p.(Asp337Glu)
- GRCh38
- chr5:68292353 T>G
- GRCh37
- chr5:67588181 T>G
Gene diagram
Every interpreted variant in PIK3R1, mapped onto the exon structure of NM_181523.2. Select a row to find it on the plot.
PIK3R1NM_181523.2
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 PIK3R1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.333
- BayesDel
- -0.104
How the predictions were used
PP3 The VCEP PP3 requires REVEL >= 0.644 AND CADD >= 26.0, OR a SpliceAI delta score >= 0.2. REVEL for this variant is 0.333 (below threshold), SpliceAI max delta is 0.02 (below threshold), and CADD is not available but both required conditions are not met independently. Details ▾Hide ▴
Evidence considered
- REVEL score 0.333 (threshold >= 0.644 not met).
- SpliceAI max delta 0.02 (threshold >= 0.2 not met).
Still missing
- CADD score not available but not needed for determination given REVEL and SpliceAI both below thresholds.
Sources
BP4 The VCEP BP4 requires REVEL <= 0.290 AND CADD <= 21.5 AND all SpliceAI delta scores < 0.1. REVEL for this variant is 0.333 (above the 0.290 threshold), so BP4 is not met. While all SpliceAI delta scores are < 0.1, the REVEL score exceeds the benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL score 0.333 exceeds BP4 threshold of <= 0.290.
- SpliceAI max delta 0.02 (all deltas < 0.1).
Still missing
- CADD score not available but REVEL alone fails the BP4 threshold.
Sources
BP7 N/ABP7 applies only to synonymous or intronic variants not predicted to impact splicing. NM_181523.2:c.1011T>G is a missense variant (p.Asp337Glu) and is not eligible for BP7 under VCEP rules. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is limited to synonymous and intronic variants per VCEP specification.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.333. BayesDel score = -0.104355.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1626566541
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_181523.2%3Ac.1011T%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-67588181-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-68292353-T-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-68292353-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_181523.2%3Ac.1011…
- OncoKB ↗www.oncokb.org/gene/PIK3R1/D337E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3R1+c.1011T%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.333. BayesDel score = -0.104355.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers.
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.