LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_003661.4:c.1024A>G
APOL1
· NP_003652.2:p.(Ser342Gly)
· NM_003661.4
GRCh37: chr22:36661906 A>G
·
GRCh38: chr22:36265860 A>G
Gene:
APOL1
Transcript:
NM_003661.4
Final call
VUS
BP4 supporting
Variant details
Gene
APOL1
Transcript
NM_003661.4
Protein
NP_003652.2:p.(Ser342Gly)
gnomAD AF
0.011403456599209948 (v4.1)
ClinVar
risk factor
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: BP4 supporting is met because the missense REVEL score is 0.081, below the 0.29 cutoff.
Final determination:
Under generic ACMG/AMP 2015 fallback rules, one supporting benign criterion alone satisfies neither the benign nor likely benign combination thresholds, so the final call is 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 a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PS1 | Not met | Not met: the evidence documents c.1024A>G itself but no different nucleotide change producing the same p.Ser342Gly amino-acid change. |
PMID:20647424
PMID:21997394
PMID:25853332
PMID:32675303
|
| PS2 | Not assessed | Not assessed: no proband-level de novo observation with confirmed maternity and paternity and no family history is documented. |
|
| PS3 | Not assessed | Not assessed: direct assays either showed weaker S342G-alone lysis or tested the combined S342G/I384M G1 haplotype rather than the queried substitution alone. |
PMID:20647424
PMID:25853332
PMID:32675303
|
| PS4 | Not met | Not met: the exact S342G-only comparison gives OR 2.32 (95% CI 0.81-6.69), below the >5.0 threshold with a CI including 1.0. |
PMID:21997394
PMID:20647424
|
| PM1 | Not met | Not met: S342G is discussed in an SRA-interacting region, but no residue-bounded critical domain without benign variation or hotspot evidence is established. |
PMID:25853332
PMID:30332315
hotspots
cosmic
gnomad_v4
|
| PM2 | Not met | Not met: gnomAD all-comers AF is 1.14% in v4.1 and 2.11% in v2.1, far above the <=0.01% PM2 threshold. |
gnomad_v2
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no affected-proband observation documents APOL1 p.Ser342Gly in trans with a qualifying pathogenic variant or establishes phase by parental or offspring testing. |
PMID:20647424
PMID:21997394
|
| PM4 | N/A | Not applicable: PM4 requires a protein-length change, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PM5 | Not met | Not met: the evidence identifies p.Ser342Gly itself but no different pathogenic missense substitution at residue 342. |
PMID:20647424
PMID:21997394
PMID:25853332
PMID:32675303
clinvar
|
| PM6 | Not assessed | Not assessed: no clinical assumed-de novo observation is reported with parental testing information insufficient for confirmation. |
|
| PP1 | Not assessed | Not assessed: no pedigree-based segregation is reported, and the seven cases versus seven controls were not affected relatives with informative meioses. |
PMID:21997394
|
| PP2 | Not assessed | Not assessed: APOL1 missense risk alleles are documented, but no gene-wide evidence establishes a low rate of benign missense variation. |
PMID:20647424
PMID:21997394
PMID:32675303
|
| PP3 | Not met | Not met: missense REVEL score 0.081 is below the generic PP3 supporting threshold of 0.644. |
revel
|
| PP4 | Not assessed | Not assessed: no individual phenotype or family history is provided to determine whether the presentation is highly specific for a single-genetic-etiology disease. |
PMID:21997394
PMID:20647424
|
| PP5 | Not met | Not met: ClinVar shows conflicting laboratory assertions but no exact-variant expert-panel pathogenic or likely pathogenic classification. |
clinvar
|
| BA1 | Not assessed | Not assessed: grpmax FAF is 22.6%, but APOL1 G1 is an incompletely penetrant kidney-disease risk allele with conflicting clinical classifications. |
gnomad_v2
gnomad_v4
clinvar
PMID:20647424
PMID:21997394
PMID:30332315
|
| BS1 | Not assessed | Not assessed: grpmax FAF is 22.6%, but APOL1 G1 is a common ancestry-enriched, incompletely penetrant risk allele requiring disorder-specific frequency calibration. |
gnomad_v2
gnomad_v4
clinvar
PMID:21997394
PMID:30332315
|
| BS2 | N/A | Not applicable: APOL1 G1 kidney-disease risk is recessive and incompletely penetrant, so gnomAD homozygotes do not establish healthy adults with early full penetrance. |
gnomad_v2
gnomad_v4
PMID:30332315
PMID:21997394
|
| BS3 | Not assessed | Not assessed: no well-established assay showed normal APOL1 function or splicing for S342G, and reduced S342G-alone lysis is not evidence of benignity. |
PMID:20647424
PMID:25853332
PMID:32675303
|
| BS4 | Not assessed | Not assessed: no affected-family pedigree shows absence of the variant, and cohort association data cannot establish non-segregation. |
PMID:21997394
PMID:25993319
|
| BP1 | Not assessed | Not assessed: available evidence shows APOL1 missense risk alleles but lacks a systematic gene-wide comparison proving whether truncating variants primarily cause disease. |
PMID:20647424
PMID:21997394
PMID:25853332
PMID:32675303
|
| BP2 | Not assessed | Not assessed: p.Ser342Gly is reported in cis with p.Ile384Met, but p.Ile384Met is not established as a qualifying pathogenic variant and no qualifying dominant observation is documented. |
PMID:20647424
PMID:21997394
|
| BP3 | N/A | Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| BP4 | Met | Met, supporting: missense REVEL score 0.081 is below the generic BP4 supporting cutoff of 0.29. |
revel
|
| BP5 | Not assessed | Not assessed: no alternate molecular diagnosis is documented for the patient carrying this variant. |
|
| BP6 | Not met | Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification and instead reports conflicting laboratory submissions. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 requires a synonymous variant, and this is a missense variant. |
generic_acmg_combination_rules
|
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.