NM_181523.2:c.1042del

PIK3R1 · NP_852664.1:p.(Arg348GlufsTer25) · NM_181523.2

GRCh37: chr5:67588950 TC>T · GRCh38: chr5:68293122 TC>T

Gene: PIK3R1 Transcript: NM_181523.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PIK3R1

Transcript

NM_181523.2

Protein

NP_852664.1:p.(Arg348GlufsTer25)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: 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 yields a total score of 9, which maps to Likely Pathogenic under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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).	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not met	No de novo occurrence with confirmed maternity and paternity has been reported for this variant in the reviewed literature or ClinVar submissions.
PS3	Not met	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.
PS4	Not met	No probands meeting the VCEP phenotype scoring criteria (Table 3) with appropriate PIK3CD locus genotyping have been reported for this variant.
PS5	N/A	PS5 is not assessed separately; PM5 serves this function in the VCEP framework. The list of criteria excludes PS5 from assessment.
PM1	N/A	PM1 is not applicable per PIK3R1 VCEP specifications.	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is mutually exclusive with PVS1 per VCEP specifications (PMID: 30192042). PVS1 has been applied at Very Strong strength for this variant.	cspec
PM5	N/A	PM5 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.	pm5_candidates cspec
PM6	N/A	PM6 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.	cspec
PP1	Not met	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).
PP2	N/A	PP2 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.	cspec
PP3	N/A	PP3 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.	spliceai cspec
PP4	Not met	No proband meeting VCEP phenotype scoring criteria (≥10 points in the PS4 counting rubric) with PIK3CD locus genotyping has been reported for this variant.
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the Antibody Deficiencies VCEP.	cspec
BA1	Not met	The variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires a GrpMax filtering allele frequency ≥0.00316, which is not met.	gnomad_v4
BS1	Not met	The variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires a GrpMax filtering allele frequency ≥0.000316, which is not met.	gnomad_v4
BS2	N/A	BS2 is not applicable per VCEP specifications due to incomplete penetrance and variable expressivity of PIK3R1-related disease.	cspec
BS3	Not met	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.
BS4	Not met	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.
BP1	N/A	BP1 is not applicable per VCEP specifications, as pathogenic PIK3R1 variants are not limited to truncating variants but can be missense as well.	cspec
BP2	N/A	BP2 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.	cspec
BP3	N/A	BP3 is not applicable per VCEP specifications, as repetitive regions of unknown function are not known within PIK3R1.	cspec
BP4	N/A	BP4 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.	cspec
BP5	Not met	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.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the Antibody Deficiencies VCEP.	cspec
BP7	N/A	BP7 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.	cspec
PM3	N/A	PM3 is not applicable per VCEP specifications as this criterion is specific to recessive disorders; PIK3R1-related immunodeficiency and SHORT syndrome has autosomal dominant inheritance.	cspec

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