Variant classification summary

NM_003661.4:c.1164_1169del

APOL1 · NP_003652.2:p.(Asn388_Tyr389del) · NM_003661.4

GRCh37: chr22:36662041 AATAATT>A · GRCh38: chr22:36265995 AATAATT>A

Gene: APOL1 Transcript: NM_003661.4

Final call

VUS

PS3 supporting PM4 supporting

Variant details

Gene

APOL1

Transcript

NM_003661.4

Protein

NP_003652.2:p.(Asn388_Tyr389del)

gnomAD AF

0.007009053179524761 (v4.1)

ClinVar

risk factor

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: deletion of N388/Y389 altered SRA binding and enabled in-vitro lysis of T. b. rhodesiense.

2

PM4 supporting: the 6-bp in-frame deletion removes two amino acids outside an identified repeat region.

Final determination: Under generic ACMG/AMP 2015 rules, PS3 supporting plus PM4 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, resulting in VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is an in-frame indel.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband-level de novo observation, confirmed maternity and paternity, or family-history information is documented.	PMID:21997394 PMID:25993319
PS3	Met	Met at supporting strength: deletion of N388/Y389 prevented SRA binding and enabled in-vitro lysis of T. b. rhodesiense in recombinant APOL1 assays.	PMID:20647424
PS4	Not met	Not met: the exact G2 deletion had an approximate OR 1.69 (95% CI 1.17-2.45), below the PS4 OR >5.0 threshold.	PMID:20647424 PMID:21997394
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD non-cancer AF is 0.95% in v2.1 exomes and 3.96% in v3.1 genomes, both above the 0.01% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: recessive APOL1 disease is reported, but no affected-proband observation demonstrates this variant in trans with a pathogenic variant or confirms phase.	PMID:21997394 PMID:20647424 gnomad_v2 gnomad_v4 PMID:25741868
PM4	Met	Met: the confirmed 6-bp in-frame deletion removes Asn388-Tyr389, producing a two-residue protein-length reduction outside an identified repeat region.	PMID:21997394 PMID:20647424 clinvar
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband-specific assumed de novo observation is reported, even though parental maternity and paternity confirmation is absent.	PMID:21997394 PMID:25993319
PP1	Not assessed	Not assessed: no family pedigree or segregation data show the variant co-segregating with disease in multiple affected relatives.	PMID:21997394 PMID:25993319
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this 6-bp in-frame deletion is outside the PP3 missense and intronic, synonymous, or splice-region scope, regardless of SpliceAI max delta 0.001.
PP4	Not assessed	Not assessed: no individual patient phenotype or family history is provided to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: ClinVar shows no exact-variant expert-panel Pathogenic or Likely pathogenic classification, only conflicting non-expert submissions.	clinvar
BA1	Not assessed	Not assessed: grpmax FAF 13.54% exceeds 5%, but APOL1 G2 is a documented low-penetrance recessive risk allele with conflicting pathogenicity evidence.	gnomad_v2 gnomad_v4 clinvar PMID:20647424 PMID:21997394
BS1	Not assessed	Not assessed: grpmax FAF 13.54% exceeds 1%, but APOL1 G2 has recessive low-penetrance risk and no maximum-credible-frequency inputs are supplied.	gnomad_v2 gnomad_v4 PMID:20647424 PMID:21997394
BS2	N/A	Not applicable: 131 and 405 homozygotes are observed, but APOL1 G2 lacks full early-age penetrance required for BS2.	gnomad_v2 gnomad_v4 PMID:20647424 PMID:21997394 clinvar
BS3	Not assessed	Not assessed: available assays show altered APOL1 trypanolytic function, not preserved protein function or splicing.	PMID:20647424
BS4	Not assessed	Not assessed: no informative affected relatives or family genotypes demonstrate lack of segregation with disease.	PMID:21997394 PMID:25993319
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no affected-proband or family data establish this variant in trans with a pathogenic variant or in cis with a pathogenic variant.	PMID:21997394 PMID:20647424 gnomad_v2 gnomad_v4 PMID:25741868
BP3	Not met	Not met: the 6-bp deletion removes Asn388-Tyr389, a functionally characterized APOL1 G2 segment rather than an established repeat without known function.	PMID:20647424 PMID:21997394 clinvar
BP4	N/A	Not applicable: this 6-bp in-frame deletion is outside the BP4 missense and intronic, synonymous, or splice-region scope, despite SpliceAI max delta 0.001.
BP5	Not assessed	Not assessed: no alternate molecular diagnosis is documented for the individual carrying this variant.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification, despite individual laboratory submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is an in-frame indel.	generic_acmg_combination_rules

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