Variant classification summary

NM_181523.2:c.1011T>G

PIK3R1 · NP_852664.1:p.(Asp337Glu) · NM_181523.2

GRCh37: chr5:67588181 T>G · GRCh38: chr5:68292353 T>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.(Asp337Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_181523.2:c.1011T>G (p.Asp337Glu) is a missense variant in exon 8 of PIK3R1. It is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold for rarity (PM2_Supporting).

2

REVEL score is 0.333, which falls between the VCEP thresholds for PP3 (>= 0.644) and BP4 (<= 0.290); neither in silico criterion is met. SpliceAI predicts no splicing impact (max delta 0.02).

3

No functional studies have tested this variant in any VCEP-approved assay. The variant is absent from ClinVar with no prior classifications. No publications, case reports, or segregation data exist for this variant.

4

Under the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP, the only met criterion is PM2_Supporting (+1 point), yielding a total score of +1, which falls in the Uncertain Significance range (0-5 points).

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.1011T>G is a missense variant (p.Asp337Glu). The ClinGen Antibody Deficiencies VCEP PVS1 rules apply only to nonsense, frameshift, and canonical splice variants; missense variants are not eligible for PVS1 under this framework.	cspec pvs1_variant_assessment
PS1	Not met	No other nucleotide change encoding the same amino acid (p.Asp337Glu) has been classified as Pathogenic or Likely Pathogenic by the Antibody Deficiencies VCEP. This variant is absent from ClinVar and no prior classification exists for this residue change.	cspec clinvar
PS2	Not met	No de novo occurrence data are available for NM_181523.2:c.1011T>G. No proband has been reported with confirmed maternity and paternity harboring this variant.
PS3	Not met	No functional studies have been performed on NM_181523.2:c.1011T>G (p.Asp337Glu). The VCEP-approved functional assays (AKT kinase activity, lipid kinase activity, protein binding, conformational dynamics, and the pAKT/pS6 enrichment assay from PMID:40543502) have not tested this variant. Of note, the related synonymous variant p.Asp337Asp was tested in the PMID:40543502 screen but not p.Asp337Glu.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4	Not met	No probands harboring NM_181523.2:c.1011T>G have been reported. The variant is absent from ClinVar, and no case reports or cohort studies have documented affected individuals with this variant.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen Antibody Deficiencies VCEP specifications for PIK3R1 (version 1.0.0). Under the governing VCEP framework, this criterion is not applicable.	cspec
PM1	N/A	PM1 is designated as Not Applicable by the ClinGen Antibody Deficiencies VCEP for PIK3R1. Additionally, this variant does not lie in a statistically significant mutational hotspot.	cspec
PM2	Met	NM_181523.2:c.1011T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The total allele frequency of 0.0 is below the VCEP PM2_Supporting threshold of <0.00000132 (derived from the Whiffin/Ware calculator using autosomal dominant parameters: prevalence 1/4000, penetrance 0.95).	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	Per the ClinGen Antibody Deficiencies VCEP instructions for PM5: 'Do not apply to missense variants given that missense variation is not a well-described contributor to PIK3R1-related APDS.' NM_181523.2:c.1011T>G is a missense variant and is therefore excluded from PM5 under VCEP rules.	cspec
PM6	N/A	The ClinGen Antibody Deficiencies VCEP designates PM6 as Not Applicable, instructing that PS2 should be used in lieu of PM6 for apparent de novo occurrences.	cspec
PP1	Not met	No co-segregation data are available for NM_181523.2:c.1011T>G. No family studies or segregation analyses have been reported for this variant.
PP2	N/A	The ClinGen Antibody Deficiencies VCEP designates PP2 as Not Applicable for PIK3R1. 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	The VCEP PP3 requires REVEL >= 0.644 AND CADD >= 26.0, OR a SpliceAI delta score >= 0.2. REVEL for this variant is 0.333 (below threshold), SpliceAI max delta is 0.02 (below threshold), and CADD is not available but both required conditions are not met independently.	revel spliceai cspec
PP4	Not met	No proband clinical data are available for NM_181523.2:c.1011T>G. PP4 requires a proband scoring >=10 phenotype points on the PS4 counting rubric with genotyping ruling out PIK3CD variants, and no such proband has been reported.
PP5	N/A	The ClinGen Antibody Deficiencies VCEP designates PP5 as Not Applicable for this VCEP, per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	NM_181523.2:c.1011T>G is absent from gnomAD v4.1.0 (allele frequency 0.0). The VCEP BA1 threshold requires GrpMax filtering allele frequency >= 0.00316, which is not met.	gnomad_v4 cspec
BS1	Not met	NM_181523.2:c.1011T>G is absent from gnomAD v4.1.0 (allele frequency 0.0). The VCEP BS1 threshold requires GrpMax filtering allele frequency >= 0.000316, which is not met.	gnomad_v4 cspec
BS2	N/A	The ClinGen Antibody Deficiencies VCEP designates BS2 as Not Applicable for PIK3R1 due to incomplete penetrance and variable expressivity of disease.	cspec
BS3	Not met	No functional studies showing a non-damaging effect have been performed on NM_181523.2:c.1011T>G. The variant has not been tested in any VCEP-approved in vitro assay. BS3 cannot be applied without variant-specific experimental evidence of normal function.	vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4	Not met	No segregation data are available for NM_181523.2:c.1011T>G. BS4 requires at least one affected family member lacking the variant (with >=6 PS4 phenotype points), and no such data exist.
BP1	N/A	The ClinGen Antibody Deficiencies VCEP designates BP1 as Not Applicable because pathogenic PIK3R1 variants are not limited to truncating variants but include missense variants as well.	cspec
BP2	N/A	The ClinGen Antibody Deficiencies VCEP designates BP2 as Not Applicable because the full spectrum of allelic mechanisms for PIK3R1 is not yet understood, and diverse combinatorial variant effects cannot be excluded.	cspec
BP4	Not met	The VCEP BP4 requires REVEL <= 0.290 AND CADD <= 21.5 AND all SpliceAI delta scores < 0.1. REVEL for this variant is 0.333 (above the 0.290 threshold), so BP4 is not met. While all SpliceAI delta scores are < 0.1, the REVEL score exceeds the benign threshold.	revel spliceai cspec
BP5	Not met	No cases have been reported in which NM_181523.2:c.1011T>G was found in a patient with an alternative molecular basis for disease. The VCEP requires at least 2 such cases for BP5_Supporting.
BP6	N/A	The ClinGen Antibody Deficiencies VCEP designates BP6 as Not Applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	BP7 applies only to synonymous or intronic variants not predicted to impact splicing. NM_181523.2:c.1011T>G is a missense variant (p.Asp337Glu) and is not eligible for BP7 under VCEP rules.	cspec
BP3	N/A	BP3 is designated Not Applicable by the VCEP because repetitive regions of unknown function are not known within PIK3R1.	cspec
PM3	N/A	PM3 is specific to recessive disorders; PIK3R1-related immunodeficiency is autosomal dominant.	cspec
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_181523.2:c.1011T>G is a missense substitution.	cspec

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