NM_001015877.1:c.823G>A (p.Gly275Arg) in PHF6 is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2.1 Gly275 resides within the extended PHD finger domain 2 (ePHD2, residues 249-295), a functionally critical domain for PHF6 nucleolar localization and transcriptional regulation, supporting PM1 at supporting weight. The variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory, SCV001142206) with maternal origin; no de novo occurrence, pathogenic assertion, or functional evidence was identified.2 No pathogenic missense comparator at codon 275, no case-control data, no cosegregation data, and no functional studies were identified, leaving PS1, PS4, PS5, PP1, PS3, and PM5 unmet. In silico predictions are inconclusive: BayesDel score is borderline (0.4267), SpliceAI predicts no splice impact (max delta 0.01), and REVEL is unavailable, insufficient for PP3 or BP4.3 Applying generic ACMG/AMP 2015 final combination rules (PMID:25741868), two supporting pathogenic criteria (PM1_Supporting + PM2_Supporting) are insufficient to reach Likely Pathogenic; no benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).4
PHF6
Final classification
VUS
PHF6 c.823G>A · p.Gly275Arg
PHF6
NM_001015877.1:c.823G>A (p.Gly275Arg) in PHF6 is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM1PM2
VUS
PHF6 c.823G>A
PM1 + PM2
→
VUS
Gene diagram
· NM_001015877.1 · variants mapped to exon structure
PHF6
NM_001015877.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
supporting
review
Pathogenic
The variant alters Gly275 within the extended PHD finger domain 2 (ePHD2, residues approximately 249-295), a functionally critical domain involved in nucleolar localization and transcriptional regulation. The variant is absent from gnomAD, consistent with absence of benign variation in this domain. However, Cancer Hotspots does not identify this residue as a statistically significant mutation hotspot, limiting confidence to supporting weight.
Residue 275 lies within ePHD2 domain (UniProt Q8IWS0)domain is critical for PHF6 nucleolar localization and transcriptional functionvariant absent from gnomAD
✓
PM2
supporting
Pathogenic
NM_001015877.1:c.823G>A is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), meeting the non-VCEP PM2 threshold of <0.1% population frequency. Absent from gnomAD-Canada v1.0.
Absent from gnomAD v2.1 (AC=0)absent from gnomAD v4.1 (AC=0)absent from gnomAD-Canada.
Assessed · not applied
Pathogenic
PS1
No different nucleotide change at codon 275 with a higher pathogenic classification was identified.
PS2
The single ClinVar submission (SCV001142206, Hadassah Hebrew University Medical Center) reports maternal origin, indicating this variant was inherited rather than arising de novo.
PS3
No published in vitro or in vivo functional studies directly assessing the impact of p.Gly275Arg on PHF6 protein function were identified.
PS4
No case-control association study comparing allele frequency of c.823G>A in affected versus unaffected individuals was identified.
PM5
No pathogenic missense variant at codon 275 with a different amino acid substitution was identified to satisfy PM5.
PM6
No assumed de novo occurrence was identified for this variant.
PP1
No cosegregation data are available for this variant in families with PHF6-related disorders (Börjeson-Forssman-Lehmann syndrome or hematologic malignancy predisposition).
PP2
The HCI prior score for PHF6 is unavailable (gene not supported), and insufficient gene-level constraint data were retrieved to determine whether PHF6 has a low rate of benign missense variation.
PP3
Multiple lines of computational evidence do not converge to support a deleterious effect.
PP4
No detailed patient phenotype or family history data specific to PHF6-related disorders (Börjeson-Forssman-Lehmann syndrome) were available for this variant.
PP5
The variant is reported in ClinVar as Uncertain significance with no assertion criteria provided.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1, well below the BA1 allele frequency threshold of >1%.
BS1
The variant is absent from gnomAD v2.1 and v4.1, falling well below the non-VCEP BS1 threshold of >0.3% allele frequency.
BS2
No data on healthy adult carriers of this variant were identified.
BS3
No functional studies demonstrating a neutral or benign effect of p.Gly275Arg on PHF6 protein function were identified.
BS4
No segregation data demonstrating lack of cosegregation with disease in affected families were available for this variant.
BP4
Multiple lines of computational evidence do not converge to predict a benign effect.
BP5
No patient was identified in whom this variant was observed alongside a convincing alternate molecular basis for the phenotype.
BP6
No reputable source reports this variant as benign or likely benign.
N/A · 7
PVS1 · PM3 · PM4 · BP1 · BP2 · 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
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 804232)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.426665.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59699628, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links