About PIK3R1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3R1 c.310A>G, p.(Thr104Ala)
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
The variant is absent from gnomAD v4.1.0 (total allele frequency = 0), which is below the VCEP PM2_Supporting threshold of <0.00000132. This supports pathogenicity at the supporting level.
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
0.000 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
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.
26 criteria with recorded statuses: 1 met · 13 not met · 1 not assessed · 11 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.310A>G (p.Thr104Ala) in PIK3R1 is a novel missense variant absent from all population databases including gnomAD v4.1, meeting PM2_Supporting per the VCEP allele frequency threshold (<0.00000132).
Computational evidence is benign-leaning: REVEL score is 0.125, BayesDel is -0.618838, and SpliceAI predicts no splice impact (max delta 0.00). PP3 thresholds (REVEL ≥0.644, SpliceAI ≥0.2) are not met.
No functional studies, clinical cases, co-segregation data, or literature reports were identified for this specific variant. PVS1, PS1-PS5, PP1, PP3-PP5, BA1, BS1, BS3-BS4, and BP5 are not met. Multiple criteria (PM1, PM5, PM6, BP1, BP2, BP6, BP7, PP2, PP5, BS2) are designated as not applicable by the PIK3R1 VCEP. BP4 could not be fully assessed due to absence of CADD score.
Using the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP (Tavtigian 2020, PMID:32720330), the sole met criterion PM2_Supporting contributes +1 point (supporting). The total score of 1 falls in the 0–5 range, corresponding to a classification of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingThe variant is absent from gnomAD v4.1.0 (total allele frequency = 0), which is below the VCEP PM2_Supporting threshold of <0.00000132. This supports pathogenicity at the supporting level. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF=0)
- v2.1 (AF=0)
- and gnomAD-Canada v1.0 (AF=0). Total AF 0 < VCEP threshold 0.00000132.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No other missense variant at codon 104 of PIK3R1 has been classified as Pathogenic or Likely Pathogenic by the Antibody Deficiencies VCEP. The variant is absent from ClinVar and no comparator variant at this residue was identified in the literature. Details ▾Hide ▴
PS2 No de novo observation has been reported for this variant. No proband or parental data are available to assess de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No proband or parental genotype data.
PS3 No variant-specific functional study has been identified for NM_181523.2:c.310A>G (p.Thr104Ala). The VCEP-approved functional assays catalog (04_08_26_PIK3R1_Functional_Assays_PS3_BS3.xlsx) does not list this variant in any assay. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet reviewed
- T104A not listed in any approved assay.
Still missing
- No functional data for this specific variant.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3cspec ↗
PS4 No affected probands harboring this variant have been identified in ClinVar or the literature. The variant is absent from all population and clinical databases, precluding any case-control or proband-counting assessment. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no probands reported.
Still missing
- No proband data available.
Sources
PP1 No co-segregation data are available. No family studies or affected relatives have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family or co-segregation data.
PP3 PP3 is not met per PIK3R1 VCEP rules. REVEL score is 0.125, well below the threshold of ≥0.644. SpliceAI max delta score is 0.00, below the threshold of ≥0.2. Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.125 (<0.644 threshold). SpliceAI max delta=0.00 (<0.2 threshold). BayesDel=-0.618838 (benign-leaning).
Sources
PP4 No proband with a phenotype specific to PIK3R1-related immunodeficiency has been reported for this variant. No clinical data are available to assess phenotype specificity. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- No clinical phenotype data.
BA1 The variant is absent from gnomAD v4.1.0 (GrpMax filtering AF = 0), which is below the VCEP BA1 Stand Alone threshold of ≥0.00316. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 GrpMax AF = 0
- BA1 threshold ≥0.00316 not met.
Sources
BS1 The variant is absent from gnomAD v4.1.0 (GrpMax filtering AF = 0), which is below the VCEP BS1 Strong threshold of ≥0.000316. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 GrpMax AF = 0
- BS1 threshold ≥0.000316 not met.
Sources
BS3 No variant-specific functional study demonstrating a non-damaging effect has been identified for NM_181523.2:c.310A>G (p.Thr104Ala). The VCEP-approved functional assays catalog does not list this variant. Details ▾Hide ▴
Evidence considered
- VCEP functional assay spreadsheet reviewed
- T104A not listed in any assay.
Still missing
- No functional data for this variant.
Sources
vcep_04_08_26_pik3r1_functional_assays_ps3_bs3cspec ↗
BS4 No family segregation data are available. No affected family members lacking the variant have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family data.
BP5 No cases have been identified in which this variant is found alongside an alternative molecular basis for disease. The VCEP requires at least 2 such cases. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular basis identified.
Still missing
- No cases with alternative molecular diagnosis.
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no published classification exists. PS5 is not addressed by the PIK3R1 VCEP specifications. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available.
Sources
Not assessed · 1 · no assessment recorded
BP4 The VCEP BP4 rule requires both REVEL ≤0.290 AND CADD ≤21.5, plus SpliceAI Δ scores <0.1. REVEL (0.125) meets the threshold, SpliceAI max delta (0.00) meets the threshold, and BayesDel (-0.618838) is benign-leaning. However, a CADD score was not computed for this variant; without CADD, the dual-threshold requirement cannot be fully verified. BP4 is not assessed pending CADD score retrieval. Details ▾Hide ▴
Evidence considered
- REVEL=0.125 (≤0.290 ✓)
- SpliceAI max delta=0.00 (<0.1 ✓)
- BayesDel=-0.618838 (benign-leaning ✓). CADD not available (required for VCEP BP4).
Still missing
- CADD score not computed
- needed to confirm BP4 per VCEP rule.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. This variant (NM_181523.2:c.310A>G, p.Thr104Ala) is a missense substitution in exon 2 and does not fall into the VCEP-defined PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Details ▾Hide ▴
Evidence considered
- Missense variant p.Thr104Ala
- not a null variant.
Sources
pvs1_variant_assessmentcspec ↗
PM1 VCEPPM1 is designated as Not Applicable by the Antibody Deficiencies VCEP for PIK3R1. Details ▾Hide ▴
PM5 N/AThe PIK3R1 VCEP instructs not to apply PM5 to missense variants, as missense variation is not a well-described contributor to PIK3R1-related APDS. No VCEP-classified comparator exists at codon 104 regardless. Details ▾Hide ▴
Evidence considered
- VCEP instructions: PM5 not applied to missense variants. No comparator at codon 104.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is designated as Not Applicable by the Antibody Deficiencies VCEP; PS2 is used instead for de novo assessments. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the Antibody Deficiencies VCEP. The gnomAD v2.1.1 missense Z score for PIK3R1 (Z=2.72) indicates this gene is not constrained for missense variation. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS2 VCEPBS2 is designated as Not Applicable by the Antibody Deficiencies VCEP due to incomplete penetrance and variable expressivity of PIK3R1-related disease. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the Antibody Deficiencies VCEP. Pathogenic PIK3R1 variants are not limited to truncating variants but can be missense as well. Details ▾Hide ▴
BP2 VCEPBP2 is designated as Not Applicable by the Antibody Deficiencies VCEP, as the field does not fully understand all potential allelic mechanisms of PIK3R1 variants. Details ▾Hide ▴
BP6 VCEPBP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or intronic variants not predicted to impact splicing. This variant is a missense substitution (p.Thr104Ala) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous or intronic variants per VCEP.
Sources
Identifiers
- Gene
- PIK3R1
- Transcript
- NM_181523.2
- Coding (HGVS c.)
- NM_181523.2:c.310A>G
- Protein (HGVS p.)
- NP_852664.1:p.(Thr104Ala)
- GRCh38
- chr5:68226985 A>G
- GRCh37
- chr5:67522813 A>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
- 0.125
- BayesDel
- -0.619
How the predictions were used
PP3 PP3 is not met per PIK3R1 VCEP rules. REVEL score is 0.125, well below the threshold of ≥0.644. SpliceAI max delta score is 0.00, below the threshold of ≥0.2. Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.125 (<0.644 threshold). SpliceAI max delta=0.00 (<0.2 threshold). BayesDel=-0.618838 (benign-leaning).
Sources
BP4 The VCEP BP4 rule requires both REVEL ≤0.290 AND CADD ≤21.5, plus SpliceAI Δ scores <0.1. REVEL (0.125) meets the threshold, SpliceAI max delta (0.00) meets the threshold, and BayesDel (-0.618838) is benign-leaning. However, a CADD score was not computed for this variant; without CADD, the dual-threshold requirement cannot be fully verified. BP4 is not assessed pending CADD score retrieval. Details ▾Hide ▴
Evidence considered
- REVEL=0.125 (≤0.290 ✓)
- SpliceAI max delta=0.00 (<0.1 ✓)
- BayesDel=-0.618838 (benign-leaning ✓). CADD not available (required for VCEP BP4).
Still missing
- CADD score not computed
- needed to confirm BP4 per VCEP rule.
Sources
BP7 N/ABP7 applies to synonymous or intronic variants not predicted to impact splicing. This variant is a missense substitution (p.Thr104Ala) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous or intronic variants per VCEP.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.125. BayesDel score = -0.618838.
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 0.000
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.310A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-67522813-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-68226985-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-68226985-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_181523.2%3Ac.310A…
- OncoKB ↗www.oncokb.org/gene/PIK3R1/T104A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3R1+c.310A%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 = 0.00). REVEL score = 0.125. BayesDel score = -0.618838.
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.