Classification rationale

PM2 BP4 VUS

PHF6 c.859G>C missense · exon 9

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BP4 (Supporting): SpliceAI predicts negligible splice impact (max delta 0.002, below the 0.2 threshold). VUS: one supporting pathogenic and one supporting benign criterion satisfy no ACMG/AMP combination rule.

PM2 + BP4 → VUS

Gene diagram · NM_001015877.1 · variants mapped to exon structure

PHF6 NM_001015877.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting review Pathogenic

Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity for a rare disorder.

The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v2.1.The consolidated evidence reports NM_001015877.1:c.859G>C as absent from gnomAD v4.1.The consolidated evidence reports the variant as absent from gnomAD-Canada v1.0, with AC=0 and AF=0.0; the accompanying AN=0 is a data-quality limitation.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): SpliceAI predicts negligible splice impact (max delta 0.002, well below the 0.2 threshold).

SpliceAI Lookup (spliceai source) reports max delta score 0.002 (DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.0) for NM_001015877.1:c.859G>C, far below the ~0.2 delta-score threshold established as a splice-altering cutoff in the original SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), supporting no predicted splicing impact.BayesDel score of 0.545598 was retrieved from the local predictor but is excluded from BP4 scoring because no verified published threshold/table is currently citable for BayesDel by this pipeline.REVEL prefetch failed ('No REVEL ZIP found for chrX:134417193'), so no missense REVEL-based evidence contributes to BP4.

spliceai ↗

Assessed · not applied · 5 not met · 17 not assessed

Pathogenic

PS1 Not assessed: no variant producing the identical p.Gly287Arg change with an established pathogenic classification was available.

PS2 Not assessed: no de novo observation with parental testing confirming absence in both parents was documented.

PS3 Not assessed: no functional assay evidence (e.g., transactivation, chromatin binding) for p.Gly287Arg was available.

PS4 Not assessed: no case-control cohort or affected-case counts for this variant were available.

PM1 Not assessed: residue 287 is not documented as a mutational hotspot or critical functional domain.

PM3 Not assessed: no evidence the variant occurs in trans with a pathogenic allele in an affected individual.

PM5 Not assessed: no pathogenic missense variant at codon 287 with a different amino acid was available.

PM6 Not assessed: no presumed de novo observation in a proband was documented.

PP1 Not assessed: no familial cosegregation or pedigree data was available.

PP2 Not assessed: no PHF6 missense constraint data (e.g., gnomAD Z-score) was available to assess benign missense rate.

PP3 Not met: no calibrated missense predictor evidence supported damage (REVEL unavailable), and SpliceAI predicted negligible splice disruption (max delta 0.002).

PP4 Not assessed: the patient's phenotype was not provided.

PP5 Not met: the variant is absent from ClinVar, with no expert-panel pathogenic classification available.

Benign

BA1 Not met: absent from gnomAD, so no population frequency at or above the BA1 threshold is demonstrated.

BS1 Not met: absent from gnomAD, so no elevated population frequency above the benign threshold is demonstrated.

BS2 Not assessed: no unaffected adult carriers or homozygotes were documented.

BS3 Not assessed: no functional assay evidence of normal protein activity for p.Gly287Arg was available.

BS4 Not assessed: no unaffected relatives carrying the variant were documented.

BP1 Not assessed: insufficient data on PHF6's benign missense rate to determine whether missense is a common disease mechanism.

BP2 Not assessed: no in-trans or in-cis observations with phase or inheritance information were available.

BP5 Not assessed: no alternate molecular diagnosis evidence was provided.

BP6 Not met: the variant is absent from ClinVar, with no expert-panel benign classification available.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.545598.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PHF6, a chromatin binding protein, is frequently altered by mutation and deletion in a range of hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots