Variant classification summary

NM_181523.2:c.2079A>T

PIK3R1 · NP_852664.1:p.(Glu693Asp) · NM_181523.2

GRCh37: chr5:67593333 A>T · GRCh38: chr5:68297505 A>T

Gene: PIK3R1 Transcript: NM_181523.2

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3R1

Transcript

NM_181523.2

Protein

NP_852664.1:p.(Glu693Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_181523.2:c.2079A>T (p.Glu693Asp) is a missense variant in PIK3R1 that is absent from gnomAD v4.1, meeting PM2_Supporting under the ClinGen Antibody Deficiencies VCEP specifications (AF < 0.00000132).

2

The variant does not meet PP3 (REVEL 0.467 < 0.644 threshold) or BP4 (REVEL 0.467 > 0.290 threshold). SpliceAI predicts no splice impact (max delta = 0.00).

3

No variant-specific functional data, de novo reports, co-segregation data, or proband phenotype data are available. The variant is absent from ClinVar and has not been reported in the literature.

4

PVS1, PS1, PS2, PS3, PS4, PP1, PP3, PP4, BA1, BS1, BS3, BS4, BP4, BP5, and BP7 are not met. PM1, PM5, PM6 (use PS2 instead), PP2, PP5, BS2, BP1, BP2, and BP6 are not applicable under VCEP specifications.

5

Total Bayesian points: +1 (PM2_Supporting). Under the Tavtigian et al. 2020 point scale adopted by the Antibody Deficiencies VCEP, 0–5 points corresponds to a classification of Uncertain Significance.

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 1, which maps to VUS 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	Not met	NM_181523.2:c.2079A>T is a missense variant encoding p.Glu693Asp. The VCEP PVS1 rules apply only to nonsense, frameshift, or canonical splice variants that introduce premature stop codons in specified regions, or to missense/synonymous/intronic variants with SpliceAI delta >0.2 AND experimental evidence of abnormal splicing. This variant has SpliceAI max delta score of 0.00 and no experimental evidence of splicing impact; therefore it does not meet any PVS1 strength threshold.	spliceai pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No other missense variant encoding the same amino acid change (p.Glu693Asp) has been classified as pathogenic or likely pathogenic by the Antibody Deficiencies VCEP. The variant is absent from ClinVar and no prior VCEP classification exists for this residue.	clinvar
PS2	Not met	No de novo occurrence of NM_181523.2:c.2079A>T has been reported in a patient with PIK3R1-related immunodeficiency. No publications or clinical records document this variant as de novo with confirmed maternity and paternity.
PS3	Not met	No variant-specific functional data are available for NM_181523.2:c.2079A>T (p.Glu693Asp). The VCEP-approved functional assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, pS6/pAKT enrichment ratio) have not been tested for this variant.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4	Not met	No probands harboring NM_181523.2:c.2079A>T have been reported in the literature or clinical databases. The VCEP PS4 requires at least 1 proband meeting phenotype scoring criteria (≥6 points on Table 3 with PIK3CD locus excluded, or ≥10 points without gene panel).	clinvar
PS5	N/A	PS5 is not included in the Antibody Deficiencies VCEP specifications for PIK3R1.
PM1	N/A	PM1 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP for PIK3R1.	cspec
PM2	Met	NM_181523.2:c.2079A>T is absent from gnomAD v4.1 (total allele frequency = 0), meeting the VCEP PM2_Supporting threshold of total allele frequency <0.00000132.	gnomad_v4 cspec
PM5	N/A	The Antibody Deficiencies VCEP instructs that PM5 is not to be applied to missense variants in PIK3R1, given that missense variation is not a well-described contributor to PIK3R1-related APDS.	cspec
PM6	N/A	PM6 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP. Assumed de novo occurrences are assessed under PS2 instead.	cspec
PP1	Not met	No co-segregation data are available for NM_181523.2:c.2079A>T with PIK3R1-related immunodeficiency. The VCEP requires at least 1 affected meiosis (proband + 1 affected first-degree relative) for PP1_Supporting.
PP2	N/A	PP2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP. The gnomAD v2.1.1 missense Z score for PIK3R1 (Z = 2.72) indicates the gene is not constrained for missense variation, and both benign and pathogenic missense variants exist.	cspec
PP3	Not met	REVEL score of 0.467 is below the VCEP PP3 threshold of ≥0.644, and SpliceAI max delta score is 0.00 (below the ≥0.2 threshold). The VCEP PP3 criteria are not satisfied.	revel spliceai
PP4	Not met	No proband phenotype data are available for NM_181523.2:c.2079A>T. The VCEP PP4 requires a proband scoring ≥10 phenotype points on the PS4 counting rubric with genotyping excluding PIK3CD locus variants.
PP5	N/A	PP5 is explicitly designated as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	NM_181523.2:c.2079A>T is absent from gnomAD v4.1 and does not meet the VCEP BA1 threshold of GrpMax filtering allele frequency ≥0.00316.	gnomad_v4
BS1	Not met	NM_181523.2:c.2079A>T is absent from gnomAD v4.1 and does not meet the VCEP BS1 threshold of GrpMax filtering allele frequency ≥0.000316.	gnomad_v4
BS2	N/A	BS2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP 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 are available for NM_181523.2:c.2079A>T (p.Glu693Asp). The variant has not been tested in any VCEP-approved functional assay.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4	Not met	No segregation data are available for NM_181523.2:c.2079A>T. The VCEP BS4 requires at least 1 affected family member (scoring ≥6 phenotype points) lacking the variant.
BP1	N/A	BP1 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP because pathogenic PIK3R1 variants are not limited to truncating variants but include missense variants as well.	cspec
BP2	N/A	BP2 is explicitly designated as Not Applicable by the Antibody Deficiencies VCEP because the field does not understand all potential allelic mechanisms associated with PIK3R1 variants, and diverse combinatorial variant effects cannot be excluded.	cspec
BP4	Not met	REVEL score of 0.467 exceeds the VCEP BP4 threshold of ≤0.290. The VCEP BP4 criteria require both REVEL ≤0.290 and CADD ≤21.5 with SpliceAI delta scores <0.1. The REVEL threshold is not satisfied.	revel spliceai
BP5	Not met	No proband data are available demonstrating an alternative molecular basis for disease. The VCEP BP5 requires at least 2 cases with an alternative molecular basis.
BP6	N/A	BP6 is explicitly designated as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	The VCEP BP7_Supporting rule applies to synonymous and intronic variants, not missense variants. BP7_Strong (RNA) requires experimental evidence of no impact on splicing, which is not available for this variant. NM_181523.2:c.2079A>T is a missense variant and does not satisfy any BP7 strength rule.	spliceai

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