0%
PIK3R1c.1042delLikely pathogenic
Print report
Variant interpretation report

PIK3R1 c.1042del, p.(Arg348GlufsTer25)

NM_181523.2:c.1042del NP_852664.1:p.(Arg348GlufsTer25) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PIK3R1

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_181523.2:c.1042del is a frameshift deletion in exon 9 introducing a premature termination codon at residue 372 (p.Arg348GlufsTer25). The PTC lies between c.917 and c.1890 and is predicted to trigger nonsense-mediated decay. Per Antibody Deficiencies VCEP PVS1 rules, PVS1 applies at Very Strong strength if the affected exon is present in all three biologically relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2).

PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the VCEP PM2_Supporting allele frequency threshold of less than 0.00000132 across all populations. Used at PM2_Supporting strength per VCEP specifications.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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
1 reported laboratory submissions

1 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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 lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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: 2 met · 10 not met · 0 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_181523.2:c.1042del (p.Arg348GlufsTer25) is a frameshift deletion in exon 9 of PIK3R1 introducing a premature termination codon at residue 372, predicted to trigger nonsense-mediated decay.

PVS1 is met at Very Strong strength: the PTC lies between c.917 and c.1890, is predicted to trigger NMD, and the exon 9 location satisfies the CSPEC PVS1 rule for the Antibody Deficiencies VCEP framework. Transcript presence across all three biologically relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2) should be confirmed.

PM2_Supporting is met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the VCEP allele frequency threshold of <0.00000132.

No additional pathogenic or benign criteria are met. PS3/BS3 lack variant-specific functional data. PS2/PM6 lack de novo reports. PS4/PP4 lack probands meeting VCEP phenotype criteria. PP1 lacks segregation data. PP3/BP4 are not applicable to frameshift variants. PM4 is mutually exclusive with PVS1. PM5/PS1 are not applicable to non-missense variants.

Combined Bayesian score: PVS1 (Very Strong = 8 points) + PM2_Supporting (Supporting = 1 point) = 9 points. Under the Tavtigian 2020 Bayesian point scale adopted by the Antibody Deficiencies VCEP, a score of 6–9 points corresponds to Likely Pathogenic.

Met · 2

PVS1 Very strongNM_181523.2:c.1042del is a frameshift deletion in exon 9 introducing a premature termination codon at residue 372 (p.Arg348GlufsTer25). The PTC lies between c.917 and c.1890 and is predicted to trigger nonsense-mediated decay. Per Antibody Deficiencies VCEP PVS1 rules, PVS1 applies at Very Strong strength if the affected exon is present in all three biologically relevant transcripts (NM_181523.3, NM_181504.4, NM_181524.2). Details ▾Hide ▴
Evidence considered
  • Frameshift deletion c.1042del in exon 9 between c.917 and c.1890
  • PTC at codon 372 predicted to trigger NMD (termination >50-55 nt upstream of last exon-exon junction)
  • Gene-level LOF mechanism supported by CSPEC/VCEP framework
Still missing
  • Confirm exon 9 is present in NM_181504.4 and NM_181524.2 transcripts
  • VCEP instructions include general caveat that PVS1 does not apply to APDS phenotype
  • reconcile with specific rule allowing PVS1 for c.917-c.1890 frameshift variants
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingThe variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the VCEP PM2_Supporting allele frequency threshold of less than 0.00000132 across all populations. Used at PM2_Supporting strength per VCEP specifications. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Still missing
  • Indel calling sensitivity in population databases may be reduced relative to SNVs
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 10 · evaluated, threshold not reached

PS2 No de novo occurrence with confirmed maternity and paternity has been reported for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any reviewed source
Still missing
  • De novo status could be assessed if proband parental samples become available
PS3 No variant-specific functional data from VCEP-approved in vitro assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, or T-cell enrichment ratio) has been identified for NM_181523.2:c.1042del. The VCEP functional assay spreadsheet does not list this variant among those tested. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet reviewed: c.1042del not listed among tested variants
  • No approved assay data available for this specific variant
Still missing
  • Functional characterization in a VCEP-approved assay would be required to assess PS3
PS4 No probands meeting the VCEP phenotype scoring criteria (Table 3) with appropriate PIK3CD locus genotyping have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No probands meeting VCEP PS4 criteria identified in literature or ClinVar
Still missing
  • Proband phenotypes and PIK3CD genotyping would be needed to evaluate PS4
PP1 No co-segregation data has been reported for this variant in the reviewed literature. Co-segregation analysis requires affected family members meeting VCEP phenotype scoring criteria (≥6 points per the PS4 rubric). Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • Family studies with phenotype-scored members would be needed
PP4 No proband meeting VCEP phenotype scoring criteria (≥10 points in the PS4 counting rubric) with PIK3CD locus genotyping has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No probands meeting VCEP PP4 criteria identified
Still missing
  • Proband phenotype data with PIK3CD genotyping would be needed
BA1 The variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires a GrpMax filtering allele frequency ≥0.00316, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
  • allele frequency = 0
Sources
gnomad_v4 ↗
BS1 The variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires a GrpMax filtering allele frequency ≥0.000316, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
  • allele frequency = 0
Sources
gnomad_v4 ↗
BS3 No variant-specific functional data demonstrating a non-damaging effect in VCEP-approved in vitro assays has been identified for NM_181523.2:c.1042del. The VCEP functional assay spreadsheet does not include this variant. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay spreadsheet reviewed
  • variant not listed
Still missing
  • Functional characterization required to assess BS3
BS4 No data on lack of segregation in affected family members has been reported for this variant. BS4 requires affected family members meeting VCEP phenotype criteria who do not harbor the variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • Family segregation studies needed
BP5 No cases with an alternative molecular basis for disease have been reported for this variant. VCEP requires at least 2 such cases to apply BP5 at Supporting strength. Details ▾Hide ▴
Evidence considered
  • No alternative molecular basis cases identified
Still missing
  • Cases with alternative molecular diagnoses needed
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants encoding the same amino acid change as a previously classified pathogenic variant, or to canonical splice variants with the same predicted impact per VCEP specifications. This is a frameshift deletion and does not meet PS1 criteria. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is not applicable per PIK3R1 VCEP specifications. Details ▾Hide ▴
Sources
cspec ↗
PM3 VCEPPM3 is not applicable per VCEP specifications as this criterion is specific to recessive disorders; PIK3R1-related immunodeficiency and SHORT syndrome has autosomal dominant inheritance. Details ▾Hide ▴
Sources
cspec ↗
PM4 N/APM4 is mutually exclusive with PVS1 per VCEP specifications (PMID: 30192042). PVS1 has been applied at Very Strong strength for this variant. Details ▾Hide ▴
Sources
cspec ↗
PM5 N/APM5 applies to missense variants at the same codon as a previously classified pathogenic or likely pathogenic variant per VCEP specifications. This variant is a frameshift deletion, not a missense change. The pm5_candidates search confirmed ineligibility. Details ▾Hide ▴
Sources
pm5_candidatescspec ↗
PM6 VCEPPM6 is not applicable per Antibody Deficiencies VCEP specifications. When a variant has apparent de novo origin without confirmed maternity and paternity, PS2 is used in lieu of PM6. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPPP2 is not applicable per VCEP specifications. The gnomAD v2.1.1 missense Z score for PIK3R1 (Z = 2.72) indicates this gene is not constrained for missense variation, and both benign and pathogenic missense variants are present. Details ▾Hide ▴
Sources
cspec ↗
PP3 N/APP3 in the PIK3R1 VCEP applies to missense variants (REVEL ≥0.644 and CADD ≥26.0) or to missense/synonymous/intronic variants with damaging SpliceAI predictions (Δ ≥0.2). This is a frameshift deletion with SpliceAI max delta score of 0.00 and no REVEL/CADD scores applicable. PP3 is not evaluated for frameshift variants under this framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 — no splice impact predicted
  • REVEL not applicable (not a missense variant)
Sources
spliceai ↗cspec ↗
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the Antibody Deficiencies VCEP. Details ▾Hide ▴
Sources
cspec ↗
BS2 VCEPBS2 is not applicable per VCEP specifications due to incomplete penetrance and variable expressivity of PIK3R1-related disease. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPBP1 is not applicable per VCEP specifications, as pathogenic PIK3R1 variants are not limited to truncating variants but can be missense as well. Details ▾Hide ▴
Sources
cspec ↗
BP2 VCEPBP2 is not applicable per VCEP specifications. The field does not fully understand all potential allelic mechanisms associated with PIK3R1 variants, and the possibility of diverse combinatorial variant effects cannot be excluded. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPBP3 is not applicable per VCEP specifications, as repetitive regions of unknown function are not known within PIK3R1. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/ABP4 in the PIK3R1 VCEP applies to missense variants (REVEL ≤0.290 and CADD ≤21.5) or synonymous/intronic variants not predicted to impact splicing. This is a frameshift deletion; BP4 computational predictors are not designed for or validated against this variant class. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the Antibody Deficiencies VCEP. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 in the PIK3R1 VCEP applies to synonymous or intronic variants not predicted to impact splicing (SpliceAI Δ <0.1). This is a frameshift deletion; BP7 does not apply to this variant class. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/APS5 is not assessed separately; PM5 serves this function in the VCEP framework. The list of criteria excludes PS5 from assessment. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PIK3R1
Transcript
NM_181523.2
Coding (HGVS c.)
NM_181523.2:c.1042del
Protein (HGVS p.)
NP_852664.1:p.(Arg348GlufsTer25)
GRCh38
chr5:68293122 TC>T
GRCh37
chr5:67588950 TC>T
ClinVar
3760109

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…
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

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 in the PIK3R1 VCEP applies to missense variants (REVEL ≥0.644 and CADD ≥26.0) or to missense/synonymous/intronic variants with damaging SpliceAI predictions (Δ ≥0.2). This is a frameshift deletion with SpliceAI max delta score of 0.00 and no REVEL/CADD scores applicable. PP3 is not evaluated for frameshift variants under this framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.00 — no splice impact predicted
  • REVEL not applicable (not a missense variant)
Sources
spliceai ↗cspec ↗
BP4 N/ABP4 in the PIK3R1 VCEP applies to missense variants (REVEL ≤0.290 and CADD ≤21.5) or synonymous/intronic variants not predicted to impact splicing. This is a frameshift deletion; BP4 computational predictors are not designed for or validated against this variant class. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 in the PIK3R1 VCEP applies to synonymous or intronic variants not predicted to impact splicing (SpliceAI Δ <0.1). This is a frameshift deletion; BP7 does not apply to this variant class. Details ▾Hide ▴
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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

  • A human immunodeficiency caused by mutations in the PIK3R1 gene.
    Describes two heterozygous splice site mutations (c.1425+1G>T and c.1425+1G>C) in PIK3R1 causing exon 11 skipping and primary antibody deficiency in four patients from three families. NM_181523.2:c.1042del was not identified in this paper.
    Does not name this variant
    PMID 25133428 ↗
  • Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
    Characterizes the neomorphic activity of PIK3R1 R348* (a nonsense mutation at the same codon) and L370fs in cancer models, demonstrating MAPK pathway activation and sensitivity to MEK/JNK inhibitors. NM_181523.2:c.1042del (R348Efs*25) is a distinct frameshift variant at the same residue but was not studied in this paper.
    Does not name this variant
    PMID 25284480 ↗
    Quoted passage
    We recently demonstrated that the most common recurrent PIK3R1 mutation, R348*, which accounts for approximately 10% of all PIK3R1 mutations in endometrial and colon cancers, acts as a gain-of-function mutation

    Introduction para 1; 'PIK3R1(R348*)' mentioned as recurrent mutation

  • Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.
    Reports a heterozygous splice site mutation (c.1425+1G>C) in PIK3R1 causing exon 11 skipping in a family with immunodeficiency and lymphoproliferation, with functional data showing increased AKT and S6 phosphorylation. NM_181523.2:c.1042del was not identified in this paper.
    Does not name this variant
    PMID 25488983 ↗
    Quoted passage
    a heterozygous germline mutation in a single base pair in PIK3R1 at the +1 position of intron 11
  • PIK3R1-Related SHORT Syndrome.
    Adam MP et al. · 1993
    GeneReviews overview of PIK3R1-related SHORT syndrome. No abstract or full-text was available for review. NM_181523.2:c.1042del could not be confirmed as mentioned in this source.
    Does not name this variant
    PMID 24830046 ↗
  • Activated PI3K Delta Syndrome.
    Adam MP et al. · 1993
    GeneReviews overview of Activated PI3K Delta Syndrome. No abstract or full-text was available for review. NM_181523.2:c.1042del could not be confirmed as mentioned in this source.
    Does not name this variant
    PMID 39899769 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Describes the Sherloc refinement of ACMG-AMP variant classification criteria. A background methods paper that does not discuss PIK3R1 or NM_181523.2:c.1042del at the variant level.
    Does not name this variant
    PMID 28492532 ↗

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 1 Uncertain significance 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

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

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.