About PHF6
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PHF6 c.1000G>T, p.(Glu334Ter)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets. This is below the non-VCEP rarity threshold of 0.1% and supports PM2 at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Generic ACMG/AMP 2015 final-classification combination rules were used because no official VCEP/CSPEC or local custom gene-specific final-classification framework was available.
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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 1 met · 7 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PHF6 c.1000G>T (p.Glu334Ter) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0 in both datasets, which is below the 0.1% rarity threshold used to support PM2 at supporting strength.
PHF6 loss of function is an established disease mechanism, and this nonsense variant is predicted to truncate the protein from 366 to 334 amino acids; however, because the change lies in the last coding exon and removes only the distal C-terminal portion, PVS1 remains for manual review rather than automatic application.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets. This is below the non-VCEP rarity threshold of 0.1% and supports PM2 at supporting strength. Details ▾Hide ▴
Rule
Generic rarity threshold: PM2 when allele frequency is below 0.1%; applied at supporting strength
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 7 · evaluated, threshold not reached
PS3 No well-established functional studies evaluating this specific PHF6 p.(Glu334Ter) variant were identified. Available literature and OncoKB references discuss PHF6 biology or other PHF6 variants, but they do not provide validated functional evidence for this exact variant. Details ▾Hide ▴
Evidence considered
- PS3 literature screen did not pass any publication for this exact variant.
- OncoKB classification is not a substitute for a validated variant-specific functional assay.
Still missing
- Need variant-specific functional assay data for p.(Glu334Ter).
Sources
PM1 Available evidence does not support that this variant lies in a mutational hotspot or a well-established critical region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at residue E334, and no PHF6-specific critical-domain rule was available. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review found no statistically significant hotspot at E334.
- PM1 literature screen was only suggestive and did not establish a hotspot-level signal.
Still missing
- Need stronger evidence that the affected C-terminal region is a well-established critical functional domain enriched for pathogenic variation.
Sources
PP5 No reputable external pathogenic classification for this exact variant was identified in ClinVar, so PP5 is not supported. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0. This is below the benign stand-alone threshold of 1%, so BA1 is not met. Details ▾Hide ▴
Rule
Benign stand-alone threshold >1%
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0. This is below the benign strong threshold of 0.3%, so BS1 is not met. Details ▾Hide ▴
Rule
Benign strong threshold >0.3%
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS3 No well-established functional studies demonstrating normal function for this specific PHF6 p.(Glu334Ter) variant were identified. The reviewed literature did not provide benign functional evidence for this exact variant. Details ▾Hide ▴
Evidence considered
- BS3 literature screen did not identify qualifying benign functional evidence for this exact variant.
Still missing
- Need validated variant-specific functional evidence showing no damaging effect.
Sources
BP6 No reputable external benign classification for this exact variant was identified in ClinVar, so BP6 is not supported. Details ▾Hide ▴
Not assessed · 10 · no assessment recorded
PVS1 This variant is a nonsense change, p.(Glu334Ter), in PHF6, and loss of function is an established germline disease mechanism for this gene. However, the variant is located in exon 10, the last coding exon, and is predicted to truncate the protein from 366 to 334 amino acids, removing 32 amino acids from the C-terminus; because escape from nonsense-mediated decay and the clinical importance of this distal region have not been resolved, PVS1 requires manual review rather than automatic application. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 framework (PMC6185798) with PHF6 LoF gene gate satisfied
Evidence considered
- PHF6 loss of function supported as a germline disease mechanism.
- Variant bucket: nonsense.
- Variant maps to exon 10.
- Protein consequence shortens the protein from 366 aa to 334 aa.
Still missing
- Need confirmation of whether this last-exon truncation is expected to escape nonsense-mediated decay.
- Need gene-specific evidence that the distal C-terminal region removed by p.(Glu334Ter) is critical for PHF6 function or that similar distal truncating variants are established as pathogenic.
Sources
PS2 No confirmed de novo data with parental testing were identified, so this criterion cannot be assessed. Details ▾Hide ▴
Still missing
- Need proband and parental testing data.
PS4 No case-control or prevalence data showing enrichment of this variant in affected individuals were identified. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions were identified.
Still missing
- Need affected-case frequency and appropriate control comparison.
Sources
PM6 No assumed de novo evidence without confirmed parental testing was identified. Details ▾Hide ▴
Still missing
- Need de novo occurrence information.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- Need family segregation data.
PP4 No phenotype information was provided to determine whether the clinical presentation is highly specific for PHF6-related disease. Details ▾Hide ▴
Still missing
- Need detailed phenotype and clinical correlation.
BS2 No evidence was identified showing this variant in healthy adult individuals for whom a fully penetrant PHF6-related phenotype would be expected. Details ▾Hide ▴
Still missing
- Need well-documented observations in unaffected individuals.
BS4 No segregation data showing lack of cosegregation with disease were identified. Details ▾Hide ▴
Still missing
- Need family segregation data.
BP2 No phase information with another pathogenic variant was identified. Details ▾Hide ▴
Still missing
- Need phasing data.
BP5 No alternate molecular explanation was identified for the relevant phenotype. Details ▾Hide ▴
Still missing
- Need full clinical and molecular differential diagnosis.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is intended for a different nucleotide change that results in the same amino acid substitution as a previously established pathogenic variant. This variant is a nonsense change, and no established alternate nucleotide change producing the same protein effect was identified. Details ▾Hide ▴
PM3 N/APM3 is used for recessive disorders with a variant observed in trans with a pathogenic variant. No recessive biallelic context was identified for this PHF6 variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes caused by in-frame insertions/deletions or stop-loss variants. This variant is a nonsense substitution, so PM4 is not the appropriate criterion. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Glu334Ter).
Sources
prefetch
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different missense pathogenic variant has been established. This variant is a nonsense change, so PM5 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 is a missense-specific criterion and does not apply to this nonsense variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Glu334Ter).
Sources
prefetch
PP3 N/APP3 is generally used for computational evidence supporting a deleterious missense or splicing effect. This variant is a nonsense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, so PP3 is not applied. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense.
- SpliceAI max delta score = 0.00.
Sources
spliceai ↗prefetch
BP1 N/ABP1 is a missense-specific criterion and does not apply to this nonsense variant. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Glu334Ter).
Sources
prefetch
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions without known function. This variant is a nonsense substitution, so BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 is generally used for computational evidence supporting a benign missense or splicing effect. This variant is a nonsense change, and although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, that prediction does not establish an overall benign effect for a stop-gain variant. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense.
- SpliceAI max delta score = 0.00.
Sources
spliceai ↗prefetch
Identifiers
- Gene
- PHF6
- Transcript
- NM_001015877.1
- Coding (HGVS c.)
- NM_001015877.1:c.1000G>T
- Protein (HGVS p.)
- NP_001015877.1:p.(Glu334Ter)
- GRCh38
- chrX:134425232 G>T
- GRCh37
- chrX:133559262 G>T
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PHF6
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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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is generally used for computational evidence supporting a deleterious missense or splicing effect. This variant is a nonsense change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, so PP3 is not applied. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense.
- SpliceAI max delta score = 0.00.
Sources
spliceai ↗prefetch
BP4 N/ABP4 is generally used for computational evidence supporting a benign missense or splicing effect. This variant is a nonsense change, and although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, that prediction does not establish an overall benign effect for a stop-gain variant. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is nonsense.
- SpliceAI max delta score = 0.00.
Sources
spliceai ↗prefetch
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_001015877.1%3Ac.1000G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-133559262-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-134425232-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001015877.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PHF6/E334*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PHF6+c.1000G%3ET
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.