LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_002107.7:c.83A>T
H3-3A
· NP_002098.1:p.(Lys28Met)
· NM_002107.7
GRCh37: chr1:226252135 A>T
·
GRCh38: chr1:226064434 A>T
Gene:
H3-3A
Transcript:
NM_002107.7
Final call
VUS
PM2 supporting
Variant details
Gene
H3-3A
Transcript
NM_002107.7
Protein
NP_002098.1:p.(Lys28Met)
gnomAD AF
ClinVar
Tier I - Strong
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.
Final determination:
Under the generic ACMG/AMP 2015 fallback rules, one supporting criterion alone satisfies no pathogenic, likely pathogenic, benign, or likely benign combination, so the 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 assessed | Not assessed: no verified pathogenic variant producing the same Lys28Met amino-acid change through a different nucleotide change was identified. |
clinvar
PMID:23603901
|
| PS2 | Not assessed | Not assessed: no documentation confirms both maternity and paternity, disease in the proband, and absence of family history. |
|
| PS3 | Not assessed | Not assessed: no validated functional assay directly tested H3-3A p.Lys28Met; reviewed studies evaluated different H3 substitutions, chiefly K27M. |
|
| PS4 | Not assessed | Not assessed: no exact-variant case-control counts were available, so an odds ratio and 95% confidence interval could not be computed against the PS4 requirement. |
|
| PM1 | Not assessed | Not assessed: Lys28 has no verified critical-domain or qualifying hotspot evidence, and no authoritative H3-3A domain table is available. |
PMID:26619011
|
| PM2 | Met | Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, meeting the <=0.0001 PM2 threshold. |
gnomad_v2
gnomad_v4
|
| PM3 | N/A | Not applicable: PM3 is restricted to recessive disorders, and no recessive H3-3A context or pathogenic variant confirmed in trans is documented. |
|
| 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 assessed | Not assessed: no verified pathogenic alternate missense change at the Lys28 residue was identified for comparison with p.Lys28Met. |
pm5_candidates
PMID:23603901
PMID:26619011
|
| PM6 | Not assessed | Not assessed: no parental testing or clinical evidence supports an assumed de novo occurrence. |
|
| PP1 | Not assessed | Not assessed: no affected relatives, variant-positive relatives, or cosegregation count is documented. |
|
| PP2 | Not assessed | Not assessed: missense disease mechanism is described, but no validated gene-level low benign-missense-rate evidence is available for H3-3A. |
pvs1_gene_context
gnomad_v2
gnomad_v4
gnomad_canada
|
| PP3 | Not met | Not met: missense REVEL 0.371 is below the generic PP3 supporting threshold of 0.644. |
revel
|
| PP4 | Not assessed | Not assessed: no individual phenotype or family-history description was available to determine whether the presentation is highly specific for one genetic disease. |
|
| PP5 | Not met | Not met: ClinVar shows zero expert-panel submissions for the exact variant, and the indexed paper does not report it as pathogenic. |
clinvar
|
| BA1 | Not met | Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the >=0.05 BA1 threshold. |
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: the variant is absent from gnomAD v2.1 and v4.1, not above the generic 0.01 BS1 frequency threshold. |
gnomad_v2
gnomad_v4
|
| BS2 | Not assessed | Not assessed: no healthy adult individual is reported with the required genotype for this criterion. |
|
| BS3 | Not assessed | Not assessed: no well-established assay directly showed that H3-3A p.Lys28Met lacks a damaging effect on protein function or splicing. |
|
| BS4 | Not assessed | Not assessed: no affected relatives with documented negative variant testing are available to evaluate lack of segregation. |
|
| BP1 | Not met | Not met: available H3-3A disease literature describes causative missense variants with gain-of-function or dominant-negative effects, not primarily truncating disease. |
pvs1_gene_context
|
| BP2 | Not assessed | Not assessed: no pathogenic variant is documented in trans or cis with H3-3A p.(Lys28Met), and no phase information is available. |
|
| 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 | Not met | Not met: missense REVEL 0.371 is above the generic BP4 supporting threshold of 0.29. |
revel
|
| BP5 | Not assessed | Not assessed: no patient-level evidence showed the exact variant in a case with an established alternate molecular basis for disease. |
|
| BP6 | Not met | Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification was identified; expert-panel submissions were zero. |
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.