Variant classification summary

NM_181523.2:c.1585_1587del

PIK3R1 · NP_852664.1:p.(Asp529del) · NM_181523.2

GRCh37: chr5:67590989 TATG>T · GRCh38: chr5:68295161 TATG>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.(Asp529del)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_181523.2:c.1585_1587del (p.Asp529del) is absent from all gnomAD population databases, fulfilling VCEP PM2_Supporting (AF < 0.00000132).

2

No other pathogenic or benign criteria were met under the Antibody Deficiencies VCEP specifications for PIK3R1. The variant is an in-frame deletion of a single amino acid in exon 13 (iSH2 domain) and is not predicted to alter splicing (SpliceAI max delta = 0.00).

3

With a single supporting-level pathogenic criterion (PM2_Supporting = +1 Bayesian point), the variant falls in the Uncertain Significance range (0-5 points) under the Tavtigian 2020 Bayesian point scale adopted by the VCEP.

Final determination: ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0 v1.0 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	NM_181523.2:c.1585_1587del (p.Asp529del) is an in-frame deletion of a single amino acid in exon 13. It does not introduce a premature termination codon, is not predicted to trigger nonsense-mediated decay, and does not disrupt canonical splice sites. Does not meet any VCEP PVS1 strength rule (which requires nonsense/frameshift variants with NMD or canonical splice variants causing exon skipping).	pvs1_variant_assessment cspec
PS1	N/A	VCEP PS1 applies to missense variants with the same amino acid change as a previously classified pathogenic/likely pathogenic variant, or to canonical splice variants with equivalent predicted impact. This variant is an in-frame deletion, not a missense or splice variant.	cspec
PS2	Not assessed	No de novo observation with confirmed maternity and paternity has been reported for this variant. No proband meeting VCEP PS2 phenotype scoring criteria is available.
PS3	Not assessed	No functional studies directly testing NM_181523.2:c.1585_1587del (p.Asp529del) were identified in the literature or in the VCEP-approved functional assay compendium (04_08_26_PIK3R1_Functional_Assays_PS3_BS3.xlsx). The VCEP catalogs approved assay types (AKT kinase activity, lipid kinase activity, protein binding, conformational dynamics) but this specific variant was not tested in any of them.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4	Not assessed	No probands with this variant meeting the VCEP PS4 phenotype scoring criteria (≥6 points) and PIK3CD genotyping requirements have been identified in the available evidence.
PS5	N/A	PS5 is not a recognized ACMG/AMP 2015 criterion and is not defined in the PIK3R1 Antibody Deficiencies VCEP specification.
PM1	N/A	PM1 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1.	cspec
PM2	Met	NM_181523.2:c.1585_1587del (p.Asp529del) is absent from all gnomAD population databases (v2.1, v4.1, Canada), satisfying the VCEP PM2_Supporting threshold of total allele frequency < 0.00000132 across all populations.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Not met	VCEP PM4 requires an in-frame deletion resulting in a protein length change of ≥2 amino acids. This variant deletes a single amino acid (p.Asp529del) and does not meet the ≥2 amino acid threshold.	cspec
PM5	N/A	VCEP PM5 applies only to missense variants at the same codon with a comparator classified as Pathogenic/Likely Pathogenic by VCEP standards. This is an in-frame deletion, not a missense variant. The pm5_candidates assessment confirms the variant is not eligible for classic PM5.	cspec pm5_candidates
PM6	N/A	PM6 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1. VCEP instructs use of PS2 instead for de novo evidence.	cspec
PP1	Not assessed	No co-segregation data is available for this variant. No family studies with affected relatives meeting VCEP PP1 phenotype scoring criteria have been identified.
PP2	N/A	PP2 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1. The gnomAD v2.1.1 missense Z-score for PIK3R1 (Z = 2.72) does not support constraint for missense variation.	cspec
PP3	Not met	VCEP PP3 criteria are: (1) missense variant with REVEL ≥0.644 and CADD ≥26.0 — not applicable for this in-frame deletion; (2) missense, synonymous, or intronic variants with SpliceAI Δ ≥0.2 — not applicable as this is an in-frame deletion, and SpliceAI max delta is 0.00 anyway.	cspec spliceai
PP4	Not assessed	No proband phenotype data meeting the VCEP PP4 threshold (≥10 phenotype points with PIK3CD genotyping) is available for this variant.
PP5	N/A	PP5 is marked as not applicable for this VCEP by the Antibody Deficiencies Expert Panel. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	Variant is absent from gnomAD (v2.1, v4.1, Canada). Does not meet the VCEP BA1 threshold of GrpMax filtering allele frequency ≥0.00316.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD (v2.1, v4.1, Canada). Does not meet the VCEP BS1 threshold of GrpMax filtering allele frequency ≥0.000316.	gnomad_v2 gnomad_v4
BS2	N/A	BS2 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1 due to incomplete penetrance and variable expressivity of disease.	cspec
BS3	Not assessed	No functional studies showing a non-damaging effect for p.Asp529del were identified. The VCEP-approved functional assay compendium was reviewed but this variant was not tested in any approved assay.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4	Not assessed	No segregation data showing affected family members lacking the variant is available. VCEP BS4 requires at least one affected family member without the variant scoring ≥6 phenotype points.
BP1	N/A	BP1 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1. Pathogenic PIK3R1 variants are not limited to truncating variants — missense variants are also pathogenic.	cspec
BP2	N/A	BP2 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1. Allelic mechanisms are incompletely understood, and the possibility of diverse combinatorial variant effects cannot be excluded.	cspec
BP3	N/A	BP3 is marked as not applicable by the Antibody Deficiencies VCEP for PIK3R1 — repetitive regions of unknown function are not known within PIK3R1.	cspec
BP4	Not met	VCEP BP4 is met by: (1) missense variants with REVEL ≤0.290 and CADD ≤21.5 and all SpliceAI Δ <0.1, or (2) synonymous/intronic variants without splice impact. This is an in-frame deletion and is not covered by either BP4 pathway. Although SpliceAI max delta is 0.00, the VCEP does not provide a BP4 rule for in-frame deletions.	cspec spliceai
BP5	Not assessed	No cases with an alternative molecular basis for disease have been identified for this variant. VCEP BP5 requires at least 2 such cases.
BP6	N/A	BP6 is marked as not applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	VCEP BP7 applies to synonymous variants (except first/last 3 nucleotides of exon) or intronic variants (outside +1 to +6 and -1 to -20 positions) without splice impact. This is an in-frame deletion, not covered by BP7.	cspec

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