About PHF6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PHF6 c.823G>A, p.(Gly275Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59699628, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 19 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001015877.1:c.823G>A (p.Gly275Arg) in PHF6 is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2.
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.
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.
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).
No criteria match.
Met · 2
PM1 SupportingThe 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. Details ▾Hide ▴
Evidence considered
- Residue 275 lies within ePHD2 domain (UniProt Q8IWS0)
- domain is critical for PHF6 nucleolar localization and transcriptional function
- variant absent from gnomAD
- consistent with no benign variation in the domain.
Still missing
- No systematic domain-level mutational significance analysis
- Cancer Hotspots does not flag residue 275 as a statistically significant hotspot.
Sources
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0)
- absent from gnomAD v4.1 (AC=0)
- absent from gnomAD-Canada.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No different nucleotide change at codon 275 with a higher pathogenic classification was identified. The ClinVar submission for this variant is VUS and no other codon-275 variants with pathogenic classification were found. Details ▾Hide ▴
Evidence considered
- No same-codon pathogenic comparator variant identified in ClinVar or literature.
Still missing
- No comparator pathogenic variant at codon 275 with a different nucleotide change.
Sources
PS2 The single ClinVar submission (SCV001142206, Hadassah Hebrew University Medical Center) reports maternal origin, indicating this variant was inherited rather than arising de novo. No confirmed de novo occurrence with established maternity and paternity was identified. Details ▾Hide ▴
PS3 No published in vitro or in vivo functional studies directly assessing the impact of p.Gly275Arg on PHF6 protein function were identified. OncoKB found no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies retrieved.
Still missing
- No functional assay data for p.Gly275Arg.
Sources
PS4 No case-control association study comparing allele frequency of c.823G>A in affected versus unaffected individuals was identified. The variant is absent from gnomAD, but this alone does not constitute case-control data. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- no case-control studies available.
Still missing
- No case-control or odds-ratio data for this variant.
Sources
PM5 No pathogenic missense variant at codon 275 with a different amino acid substitution was identified to satisfy PM5. The automated PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert-panel P/LP candidates.
Still missing
- No established pathogenic comparator at Gly275.
Sources
pm5_candidates
PM6 No assumed de novo occurrence was identified for this variant. The ClinVar submission reports maternal origin (SCV001142206), inconsistent with a de novo event. Details ▾Hide ▴
Evidence considered
- ClinVar SCV001142206: maternal origin
- no de novo assertion found.
Sources
PP1 No cosegregation data are available for this variant in families with PHF6-related disorders (Börjeson-Forssman-Lehmann syndrome or hematologic malignancy predisposition). Details ▾Hide ▴
Evidence considered
- No family cosegregation studies identified.
Still missing
- No multi-generational pedigree data for this variant.
PP3 Multiple lines of computational evidence do not converge to support a deleterious effect. BayesDel predicts a borderline score of 0.4267, SpliceAI predicts no splice impact (max delta 0.01), and REVEL is unavailable. The single borderline in silico score is insufficient to meet PP3, which requires convergent evidence from multiple tools. Details ▾Hide ▴
Evidence considered
- BayesDel score 0.4267 (borderline)
- SpliceAI max delta 0.01 (no splice impact)
- REVEL not found.
Still missing
- REVEL score unavailable.
- No convergent in silico prediction of deleteriousness.
Sources
bayesdelspliceai ↗
PP4 No detailed patient phenotype or family history data specific to PHF6-related disorders (Börjeson-Forssman-Lehmann syndrome) were available for this variant. The ClinVar submission does not include phenotype annotations. Details ▾Hide ▴
Evidence considered
- ClinVar submission lacks specific phenotype annotations
- no case reports with detailed clinical data.
Still missing
- No patient phenotype data available for assessment.
Sources
PP5 The variant is reported in ClinVar as Uncertain significance with no assertion criteria provided. No reputable source (e.g., expert panel, clinical diagnostic laboratory with criteria) reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- 1 submitter (Hadassah)
- no assertion criteria provided
- review status: no assertion criteria provided.
Sources
BA1 The variant is absent from gnomAD v2.1 and v4.1, well below the BA1 allele frequency threshold of >1%. Details ▾Hide ▴
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. Details ▾Hide ▴
BS2 No data on healthy adult carriers of this variant were identified. The variant is absent from gnomAD, and no reports document observation of this variant in healthy adults without PHF6-related phenotypes. Details ▾Hide ▴
Evidence considered
- Variant absent from population databases
- no reports of healthy adult carriers.
Still missing
- No healthy adult carrier data.
Sources
BS3 No functional studies demonstrating a neutral or benign effect of p.Gly275Arg on PHF6 protein function were identified. OncoKB found no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: no reviewed functional evidence for this variant.
Still missing
- No functional assay demonstrating neutral effect.
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease in affected families were available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies showing non-segregation with PHF6-related phenotype.
Still missing
- No segregation data available.
BP4 Multiple lines of computational evidence do not converge to predict a benign effect. SpliceAI predicts no splice impact (max delta 0.01), but BayesDel predicts a score of 0.4267, which is not in the clearly benign range. REVEL is unavailable. The single benign prediction from SpliceAI alone is insufficient to meet BP4, which requires multiple lines of evidence supporting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (no splice impact)
- BayesDel 0.4267 (not clearly benign)
- REVEL unavailable.
Still missing
- Insufficient convergent benign in silico predictions.
Sources
bayesdelspliceai ↗
BP5 No patient was identified in whom this variant was observed alongside a convincing alternate molecular basis for the phenotype. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular diagnosis identified.
Still missing
- No data on alternate molecular basis in carriers.
BP6 No reputable source reports this variant as benign or likely benign. ClinVar classifies it as Uncertain significance with no assertion criteria provided. BP6 requires a reputable source reporting the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- no expert panel or reputable source reporting benign.
Sources
PS5 No different pathogenic missense variant at codon 275 was identified as a comparator. PS5 requires a previously established pathogenic missense change at the same residue with a different amino acid substitution. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variant at codon 275 with a different amino acid change identified
- PM5 candidate search returned no candidates.
Still missing
- No comparator pathogenic variant at Gly275.
Sources
clinvar ↗pm5_candidates
Not assessed · 1 · no assessment recorded
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. Without a gene-level constraint metric (e.g., missense Z-score), PP2 cannot be reliably assessed. Details ▾Hide ▴
Evidence considered
- HCI prior: gene_not_supported
- no missense constraint data available.
Still missing
- No gene-level missense constraint score (Z-score or HCI prior) for PHF6.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_001015877.1:c.823G>A is a substitution producing p.(Gly275Arg) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants). ClinGen SVI PVS1 framework (PMC6185798) confirms this variant does not qualify for generic PVS1 assessment. Details ▾Hide ▴
Evidence considered
- Missense substitution p.(Gly275Arg)
- variant_bucket=other
- apply_generic_pvs1_framework=false per PVS1 decision tree.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable. PHF6 is an X-linked gene; PM3 (detected in trans with a pathogenic variant) is designed for autosomal recessive disorders. In hemizygous males, there is no trans configuration. Details ▾Hide ▴
Evidence considered
- PHF6 is X-linked
- PM3 trans criterion not applicable.
PM4 N/APM4 is not applicable. This variant is a single-nucleotide substitution, not a non-frameshift insertion/deletion or stop-loss variant. Details ▾Hide ▴
Evidence considered
- Substitution variant
- PM4 applies only to non-frameshift indels and stop-loss variants.
BP1 N/ABP1 is not applicable. While PHF6 loss of function is a known disease mechanism, missense variants in functionally critical domains (including the PHD finger domains) are a recognized cause of Börjeson-Forssman-Lehmann syndrome. The disease mechanism is not exclusively truncating. Details ▾Hide ▴
Evidence considered
- PHF6: both truncating and missense variants reported in BFLS
- PHD finger missense variants are disease-associated.
BP2 N/ABP2 is not applicable. PHF6 is an X-linked gene; BP2 (observed in trans with a pathogenic variant) is designed for autosomal recessive disorders. In hemizygous males there is no trans configuration, and no female carrier with a second PHF6 variant in trans has been reported. Details ▾Hide ▴
Evidence considered
- PHF6 is X-linked
- BP2 trans criterion not relevant for X-linked inheritance.
BP3 N/ABP3 is not applicable. This variant is a single-nucleotide substitution, not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 applies only to in-frame indels.
BP7 N/ABP7 is not applicable. This variant is a missense substitution (c.823G>A, p.Gly275Arg), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous/intronic variants.
Identifiers
- Gene
- PHF6
- Transcript
- NM_001015877.1
- Coding (HGVS c.)
- NM_001015877.1:c.823G>A
- Protein (HGVS p.)
- NP_001015877.1:p.(Gly275Arg)
- GRCh38
- chrX:134415109 G>A
- GRCh37
- chrX:133549139 G>A
- ClinVar
- 804232
- COSMIC
- COSV59699628
Gene diagram
Every interpreted variant in PHF6, mapped onto the exon structure of NM_001015877.1. Select a row to find it on the plot.
PHF6NM_001015877.1
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PHF6
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.427
How the predictions were used
PP3 Multiple lines of computational evidence do not converge to support a deleterious effect. BayesDel predicts a borderline score of 0.4267, SpliceAI predicts no splice impact (max delta 0.01), and REVEL is unavailable. The single borderline in silico score is insufficient to meet PP3, which requires convergent evidence from multiple tools. Details ▾Hide ▴
Evidence considered
- BayesDel score 0.4267 (borderline)
- SpliceAI max delta 0.01 (no splice impact)
- REVEL not found.
Still missing
- REVEL score unavailable.
- No convergent in silico prediction of deleteriousness.
Sources
bayesdelspliceai ↗
BP4 Multiple lines of computational evidence do not converge to predict a benign effect. SpliceAI predicts no splice impact (max delta 0.01), but BayesDel predicts a score of 0.4267, which is not in the clearly benign range. REVEL is unavailable. The single benign prediction from SpliceAI alone is insufficient to meet BP4, which requires multiple lines of evidence supporting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 (no splice impact)
- BayesDel 0.4267 (not clearly benign)
- REVEL unavailable.
Still missing
- Insufficient convergent benign in silico predictions.
Sources
bayesdelspliceai ↗
BP7 N/ABP7 is not applicable. This variant is a missense substitution (c.823G>A, p.Gly275Arg), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous/intronic variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.426665.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/804232/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-133549139-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-134415109-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001015877.1%3Ac.8…
- OncoKB ↗www.oncokb.org/gene/PHF6/G275R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128182635
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59699628, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.