LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-15
Case ID: NM_001015877.1_c.859G_C_20260815_164220
Framework: ACMG/AMP 2015
Variant classification summary

NM_001015877.1:c.859G>C

PHF6  · NP_001015877.1:p.(Gly287Arg)  · NM_001015877.1
GRCh37: chrX:133551223 G>C  ·  GRCh38: chrX:134417193 G>C
Gene: PHF6 Transcript: NM_001015877.1
Final call
VUS
PM2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PHF6
Transcript
NM_001015877.1
Protein
NP_001015877.1:p.(Gly287Arg)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
2
BP4 (Supporting): SpliceAI predicts negligible splice impact (max delta 0.002, below the 0.2 threshold).
3
VUS: one supporting pathogenic and one supporting benign criterion satisfy no ACMG/AMP combination rule.
Final determination: Generic ACMG/AMP 2015 fallback: PM2 (supporting) + BP4 (supporting) meets no P/LP/B/LB threshold, defaults to 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: missense change, so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) is triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no variant producing the identical p.Gly287Arg change with an established pathogenic classification was available.
clinvar
PS2 Not assessed Not assessed: no de novo observation with parental testing confirming absence in both parents was documented.
generic_acmg_combination_rules
PS3 Not assessed Not assessed: no functional assay evidence (e.g., transactivation, chromatin binding) for p.Gly287Arg was available.
PS4 Not assessed Not assessed: no case-control cohort or affected-case counts for this variant were available.
PM1 Not assessed Not assessed: residue 287 is not documented as a mutational hotspot or critical functional domain.
oncokb
PM2 Met Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity for a rare disorder.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 Not assessed Not assessed: no evidence the variant occurs in trans with a pathogenic allele in an affected individual.
generic_acmg_combination_rules
PM4 N/A Not applicable: missense change produces no protein length alteration.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no pathogenic missense variant at codon 287 with a different amino acid was available.
pm5_candidates clinvar
PM6 Not assessed Not assessed: no presumed de novo observation in a proband was documented.
generic_acmg_combination_rules
PP1 Not assessed Not assessed: no familial cosegregation or pedigree data was available.
generic_acmg_combination_rules
PP2 Not assessed Not assessed: no PHF6 missense constraint data (e.g., gnomAD Z-score) was available to assess benign missense rate.
pvs1_gene_context
PP3 Not met Not met: no calibrated missense predictor evidence supported damage (REVEL unavailable), and SpliceAI predicted negligible splice disruption (max delta 0.002).
spliceai bayesdel
PP4 Not assessed Not assessed: the patient's phenotype was not provided.
PP5 Not met Not met: the variant is absent from ClinVar, with no expert-panel pathogenic classification available.
clinvar
BA1 Not met Not met: absent from gnomAD, so no population frequency at or above the BA1 threshold is demonstrated.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met Not met: absent from gnomAD, so no elevated population frequency above the benign threshold is demonstrated.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not assessed Not assessed: no unaffected adult carriers or homozygotes were documented.
gnomad_v2 gnomad_v4 gnomad_canada
BS3 Not assessed Not assessed: no functional assay evidence of normal protein activity for p.Gly287Arg was available.
BS4 Not assessed Not assessed: no unaffected relatives carrying the variant were documented.
generic_acmg_combination_rules
BP1 Not assessed Not assessed: insufficient data on PHF6's benign missense rate to determine whether missense is a common disease mechanism.
pvs1_gene_context
BP2 Not assessed Not assessed: no in-trans or in-cis observations with phase or inheritance information were available.
generic_acmg_combination_rules
BP3 N/A Not applicable: missense change, not an in-frame indel in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met (Supporting): SpliceAI predicts negligible splice impact (max delta 0.002, well below the 0.2 threshold).
spliceai
BP5 Not assessed Not assessed: no alternate molecular diagnosis evidence was provided.
BP6 Not met Not met: the variant is absent from ClinVar, with no expert-panel benign classification available.
clinvar
BP7 N/A Not applicable: missense change, not a synonymous variant.
generic_acmg_combination_rules
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