Variant classification summary

NM_181523.2:c.310A>G

PIK3R1 · NP_852664.1:p.(Thr104Ala) · NM_181523.2

GRCh37: chr5:67522813 A>G · GRCh38: chr5:68226985 A>G

Gene: PIK3R1 Transcript: NM_181523.2

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3R1

Transcript

NM_181523.2

Protein

NP_852664.1:p.(Thr104Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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.

4

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.

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	N/A	PVS1 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).	pvs1_variant_assessment cspec
PS1	Not met	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.	clinvar cspec
PS2	Not met	No de novo observation has been reported for this variant. No proband or parental data are available to assess de novo occurrence.
PS3	Not met	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.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3 cspec
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar
PM1	N/A	PM1 is designated as Not Applicable by the Antibody Deficiencies VCEP for PIK3R1.	cspec
PM2	Met	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.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM5	N/A	The 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.	cspec pm5_candidates
PM6	N/A	PM6 is designated as Not Applicable by the Antibody Deficiencies VCEP; PS2 is used instead for de novo assessments.	cspec
PP1	Not met	No co-segregation data are available. No family studies or affected relatives have been reported for this variant.
PP2	N/A	PP2 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.	cspec
PP3	Not met	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.	revel bayesdel spliceai cspec
PP4	Not met	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.
PP5	N/A	PP5 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	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.	gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4.1.0 (GrpMax filtering AF = 0), which is below the VCEP BS1 Strong threshold of ≥0.000316.	gnomad_v4 cspec
BS2	N/A	BS2 is 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 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.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3 cspec
BS4	Not met	No family segregation data are available. No affected family members lacking the variant have been reported.
BP1	N/A	BP1 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.	cspec
BP2	N/A	BP2 is designated as Not Applicable by the Antibody Deficiencies VCEP, as the field does not fully understand all potential allelic mechanisms of PIK3R1 variants.	cspec
BP4	Not assessed	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.	revel bayesdel spliceai cspec
BP5	Not met	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.
BP6	N/A	BP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 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.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.