0%
PHF6c.1003A>TUncertain significance
Print report
Variant interpretation report

PHF6 c.1003A>T, p.(Arg335Ter)

NM_001015877.1:c.1003A>T NP_001015877.1:p.(Arg335Ter) View identifiers
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.

About PHF6

No gene-level summary was recorded for this case.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Moderate
PVS1 · moderate

NM_001015877.1:c.1003A>T introduces a premature termination codon at p.Arg335Ter (R335*) in PHF6, a gene in which loss of function is an established mechanism for Börjeson-Forssman-Lehmann syndrome (X-linked intellectual disability). However, the variant lies in the terminal exon (exon 11 of 11), and the truncation removes only 31 C-terminal amino acids (8.5% of the 366-residue protein), consistent with predicted NMD escape. The C-terminal region spanning residues 279–365 has been shown to be functionally important for neuronal migration (deletion 279–365 impairs migration in a mouse model), but the specific contribution of residues 335–365 is not independently established. Under PMC6185798, a nonsense variant in the last exon with an affected region of uncertain criticality is assigned PVS1_Moderate.

PM2Supporting
PM2 · supporting

NM_001015877.1:c.1003A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not observed in large population cohorts.

PP3Supporting
PP3 · supporting

BayesDel score of 0.83 predicts a damaging effect for this substitution. SpliceAI predicts no significant splice alteration (max delta score 0.07), consistent with the variant's primary consequence being at the protein level via premature termination.

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: PVS1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 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.

SpliceAI score
0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 6 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001015877.1:c.1003A>T (p.Arg335Ter) introduces a premature termination codon in PHF6, a gene in which loss of function causes Börjeson-Forssman-Lehmann syndrome (X-linked intellectual disability).

The nonsense variant lies in the terminal exon (exon 11/11) and removes only 31 C-terminal amino acids, consistent with predicted NMD escape; under PMC6185798, this is assigned PVS1 at Moderate strength.

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at Supporting strength.

BayesDel in silico prediction score of 0.83 supports a deleterious effect, meeting PP3 at Supporting strength.

The combination of PVS1_Moderate, PM2_Supporting, and PP3_Supporting yields 1 Moderate and 2 Supporting criteria. Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), this does not meet the threshold for Likely Pathogenic (which requires ≥3 Moderate, or 1 Moderate + ≥4 Supporting, or a Strong criterion). The evidence is indeterminate and the variant is classified as a Variant of Uncertain Significance.

Met · 3

PVS1 ModerateNM_001015877.1:c.1003A>T introduces a premature termination codon at p.Arg335Ter (R335*) in PHF6, a gene in which loss of function is an established mechanism for Börjeson-Forssman-Lehmann syndrome (X-linked intellectual disability). However, the variant lies in the terminal exon (exon 11 of 11), and the truncation removes only 31 C-terminal amino acids (8.5% of the 366-residue protein), consistent with predicted NMD escape. The C-terminal region spanning residues 279–365 has been shown to be functionally important for neuronal migration (deletion 279–365 impairs migration in a mouse model), but the specific contribution of residues 335–365 is not independently established. Under PMC6185798, a nonsense variant in the last exon with an affected region of uncertain criticality is assigned PVS1_Moderate. Details ▾Hide ▴
Evidence considered
  • Nonsense variant (p.Arg335Ter) in PHF6
  • an established LoF disease gene for BFLS
  • Variant in terminal exon (exon 11/11)
  • NMD escape predicted
  • Truncation removes 31 C-terminal residues
  • criticality of the specific 335–365 region not independently proven
Still missing
  • No variant-specific functional study of p.R335* truncation effect
  • Uncertain whether residues 335–365 are individually critical versus the broader 279–365 C-terminal region
Sources
pvs1_generic_framework ↗
PM2 SupportingNM_001015877.1:c.1003A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not observed in large population cohorts. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingBayesDel score of 0.83 predicts a damaging effect for this substitution. SpliceAI predicts no significant splice alteration (max delta score 0.07), consistent with the variant's primary consequence being at the protein level via premature termination. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.83 (damaging prediction)
  • SpliceAI max delta 0.07 (no splicing impact)
Still missing
  • REVEL score not available for this variant
Sources
bayesdelspliceai ↗

Not met · 6 · evaluated, threshold not reached

PM1 The variant lies in the C-terminal region (residue 335) of PHF6, outside the two characterized PHD finger domains. While the C-terminal region (279–365) has been shown to contribute to neuronal migration function in a broad deletion context (PMID:23791194), this region has not been established as a well-defined mutational hotspot or critical functional domain with a high concentration of pathogenic missense variants, as required by PM1. Details ▾Hide ▴
Evidence considered
  • Variant lies outside known PHD finger domains
  • C-terminal region (279–365) contributes to function but is not a recognized mutational hotspot
PP5 This variant is absent from ClinVar and has not been classified by any expert panel or reputable clinical source. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no expert classification available
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency is 0%, far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD; allele frequency is 0%, below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 No variant-specific functional study demonstrates a benign or neutral effect for p.R335*. The C-terminal deletion tested in PMID:23791194 (residues 279–365) showed impaired function, which is consistent with a deleterious rather than benign effect. Details ▾Hide ▴
Evidence considered
  • No benign functional evidence for p.R335*
  • PMID:23791194 shows deletion 279–365 impairs function (not benign)
BP4 BayesDel score of 0.83 predicts a damaging effect. SpliceAI max delta score of 0.07 indicates no cryptic splicing, but this does not constitute benign computational evidence when the primary variant consequence (nonsense) is inherently deleterious. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.83 predicts damaging
  • not benign
  • SpliceAI delta 0.07 indicates no cryptic splicing but does not support a benign interpretation of a nonsense variant
Sources
bayesdelspliceai ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo occurrence data identified in any reviewed publication for NM_001015877.1:c.1003A>T. Details ▾Hide ▴
Still missing
  • No de novo report available
PS3 No variant-specific functional assay for p.R335* was identified in the reviewed literature. PMID:23791194 tested a C-terminal deletion (279–365) encompassing this position but did not assess the p.R335* point variant. PMID:12676923 examined p.D333del, a different variant. PMID:27479181 had no accessible full text or abstract. OncoKB assigns Likely Oncogenic to R335* in a somatic context, but this is a curated gateway annotation and does not constitute independent germline functional evidence. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional study for p.R335* identified
Still missing
  • No germline functional assay for p.R335*
  • C-terminal deletion functional data (PMID:23791194) is not variant-specific
PS4 The variant is absent from ClinVar and no case reports were identified in the reviewed literature. No prevalence or case-control data available. Details ▾Hide ▴
Still missing
  • No patient or case-control data available
PM6 No de novo event reported for this variant in the reviewed literature. Details ▾Hide ▴
Still missing
  • No de novo report available
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family or cosegregation data
PP4 No patient phenotype data specific to this variant are available. Details ▾Hide ▴
Still missing
  • No case-level phenotype data
BS4 No segregation data available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data
BP5 No observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate-molecular-basis data
PS5 No information about parental testing or defined inheritance pattern for this variant. Details ▾Hide ▴
Still missing
  • No parental or inheritance data available
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANo alternate nucleotide change at c.1003 has been reported in ClinVar or the literature; no same-site comparator exists. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator missense variants classified as pathogenic were identified in ClinVar; PM5 candidate harvesting found zero eligible comparators. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation; NM_001015877.1:c.1003A>T is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

BS2 N/APHF6 is X-linked; observation in a healthy hemizygous male would be informative for BS2 but this criterion is not assessable absent such data, and the typical autosomal homozygous framework does not apply. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease; NM_001015877.1:c.1003A>T is a nonsense (truncating) variant. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ABP2 (observation in trans with a pathogenic variant) is not applicable to X-linked PHF6. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ANo reputable source has classified this variant as benign; the variant is absent from ClinVar entirely, so BP6 cannot be applied. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_001015877.1:c.1003A>T is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PHF6
Transcript
NM_001015877.1
Coding (HGVS c.)
NM_001015877.1:c.1003A>T
Protein (HGVS p.)
NP_001015877.1:p.(Arg335Ter)
GRCh38
chrX:134425235 A>T
GRCh37
chrX:133559265 A>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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -34 bp
0.040
SpliceAI acceptor gainat +95 bp
0.000
SpliceAI donor lossat +95 bp
0.070
SpliceAI donor gainat -34 bp
0.000
Pangolin splice lossmagnitude shown
-0.090
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.830

How the predictions were used

PP3 SupportingBayesDel score of 0.83 predicts a damaging effect for this substitution. SpliceAI predicts no significant splice alteration (max delta score 0.07), consistent with the variant's primary consequence being at the protein level via premature termination. Details ▾Hide ▴
Evidence considered
  • BayesDel score 0.83 (damaging prediction)
  • SpliceAI max delta 0.07 (no splicing impact)
Still missing
  • REVEL score not available for this variant
Sources
bayesdelspliceai ↗
BP4 BayesDel score of 0.83 predicts a damaging effect. SpliceAI max delta score of 0.07 indicates no cryptic splicing, but this does not constitute benign computational evidence when the primary variant consequence (nonsense) is inherently deleterious. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.83 predicts damaging
  • not benign
  • SpliceAI delta 0.07 indicates no cryptic splicing but does not support a benign interpretation of a nonsense variant
Sources
bayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_001015877.1:c.1003A>T is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.83.

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Novel PHF6 mutation p.D333del causes Börjeson-Forssman-Lehmann syndrome.
    Reports a novel PHF6 mutation p.D333del (c.997_999delGAT) causing Börjeson-Forssman-Lehmann syndrome. NM_001015877.1:c.1003A>T (p.R335*) was not identified in this paper.
    Does not name this variant
    PMID 12676923 ↗
  • The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.
    Demonstrates that PHF6 knockdown impairs neuronal migration and that a C-terminal deletion of residues 279–365 (which encompasses position 335) blocks PHF6-dependent neuronal migration rescue. The paper tested patient mutation C99F and deletion 279–365; NM_001015877.1:c.1003A>T (p.R335*) was not specifically tested or mentioned.
    Does not name this variant
    PMID 23791194 ↗
    Quoted passage
    Likewise, deletion of the C-terminal 86 amino acids, which also causes BFLS (Berland et al., 2011), impaired PHF6-dependent neuronal migration (Figures 1G and 1H).

    Results, Figure 1G-H (deletion 279-365 data)

  • Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms.
    Title indicates a survey of somatic PHF6 mutations in 1,760 myeloid neoplasm cases. No abstract or full text was available for review. Whether NM_001015877.1:c.1003A>T (p.R335*) is specifically reported could not be determined.
    Does not name this variant
    PMID 27479181 ↗

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 0.070 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

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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.83.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.