LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_002107.7_c.103G_A_20261106_121813
Framework: ACMG/AMP 2015
Variant classification summary

NM_002107.7:c.103G>A

H3-3A  · NP_002098.1:p.(Gly35Arg)  · NM_002107.7
GRCh37: chr1:226252155 G>A  ·  GRCh38: chr1:226064454 G>A
Gene: H3-3A Transcript: NM_002107.7
Final call
VUS
PM1 moderate PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
H3-3A
Transcript
NM_002107.7
Protein
NP_002098.1:p.(Gly35Arg)
gnomAD AF
ClinVar
other
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM1 moderate: Gly35 corresponds to the recurrent H3.3 G34 mutational hotspot.
2
PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.
Final determination: Under generic ACMG/AMP 2015 fallback rules, one moderate pathogenic criterion plus one supporting pathogenic criterion does not satisfy a listed pathogenic or likely pathogenic combination, and no benign rule is met; therefore 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: the same Gly-to-Arg substitution is reported recurrently, but no prior established pathogenic classification is documented for the comparator variant.
PMID:22286061 PMID:24705251 clinvar
PS2 Not assessed Not assessed: no proband pedigree or confirmed maternity and paternity testing is available to establish a germline de novo event.
PMID:22286061 PMID:23079654 PMID:24705251
PS3 Not assessed Not assessed: available studies report tumor associations but no validated in vitro or in vivo assay directly testing H3-3A p.Gly35Arg function.
PMID:22286061 PMID:23079654 PMID:24705251
PS4 Not assessed Not assessed: affected glioma cohorts report G34R/G35R, but no exact-variant control frequency or numerical denominator permits the required OR/RR >5.0 and confidence interval test.
PMID:22286061 PMID:23079654 PMID:24705251 gnomad_v2 gnomad_v4
PM1 Met Met, moderate: Gly35 corresponds to the recurrent H3.3 G34 hotspot, with 18 G34-mutated tumors confined to the G34 molecular subgroup and no supplied benign variation.
PMID:23079654 PMID:22286061 PMID:24705251 gnomad_v2 gnomad_v4
PM2 Met Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, well below the <=0.0001 PM2 supporting threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no pathogenic partner variant or parental/offspring phase data establish this variant in trans for a recessive disorder.
clinvar PMID:22286061 PMID:23079654 PMID:24705251
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: alternate G34 substitutions are reported, but none is documented here as a previously determined pathogenic missense variant.
PMID:23079654 PMID:25128496 clinvar
PM6 Not assessed Not assessed: available reports are somatic glioma studies without a proband-level germline observation or parental testing.
PMID:22286061 PMID:23079654 PMID:24705251
PP1 Not assessed Not assessed: no affected relatives or informative meioses are reported for co-segregation with disease.
PMID:22286061 PMID:23079654 PMID:24705251
PP2 Not assessed Not assessed: missense disease mechanism is supported, but no supplied gene-level evidence establishes a low rate of benign missense variation.
PP3 Not met Not met: missense REVEL 0.443 is below the PP3 supporting threshold of 0.644.
revel
PP4 Not met Not met: glioblastoma is documented, but the evidence does not show a phenotype or family history highly specific for a single H3-3A genetic etiology.
PMID:22286061 PMID:23079654 PMID:24705251 clinvar
PP5 Not met Not met: ClinVar reports the exact variant as other with no expert-panel pathogenic or likely pathogenic classification.
clinvar
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, with no observed allele frequency approaching the 5% BA1 threshold.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1 Not met Not met: gnomAD v2.1 and v4.1 showed no observed allele frequency greater than the disorder-specific expectation.
gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2 Not assessed Not assessed: no documented healthy adult carrier or genotype-specific observation is available to evaluate the BS2 requirement.
BS3 Not assessed Not assessed: no validated assay demonstrates that H3-3A p.Gly35Arg has no damaging effect on protein function or splicing.
PMID:22286061 PMID:23079654 PMID:24705251
BS4 Not assessed Not assessed: no affected-family-member genotypes are available to demonstrate lack of segregation.
PMID:22286061 PMID:23079654 PMID:24705251
BP1 Not met Not met: H3-3A disease evidence prominently supports missense mechanisms, not a gene primarily associated with truncating variants.
PMID:22286061 PMID:23079654 PMID:24705251
BP2 Not assessed Not assessed: no pathogenic second allele with documented trans or cis phase is reported for this variant.
clinvar PMID:22286061 PMID:23079654 PMID:24705251
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 0.443 exceeds the BP4 supporting threshold of 0.29 and remains in the gray zone.
revel
BP5 Not assessed Not assessed: no evidence shows the exact variant in a case with an established alternate molecular basis for disease.
BP6 Not met Not met: ClinVar reports the exact variant as other with no expert-panel benign or likely benign classification.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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