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).1 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.2 The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at Supporting strength.3 BayesDel in silico prediction score of 0.83 supports a deleterious effect, meeting PP3 at Supporting strength.4 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.5
PHF6
Final classification
VUS
PHF6 c.1003A>T · p.Arg335Ter
PHF6
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).
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.
Classification rationale
PVS1PM2PP3
VUS
PHF6 c.1003A>T
PVS1 + PM2 + PP3
→
VUS
4
bayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_001015877.1 · variants mapped to exon structure
PHF6
NM_001015877.1
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
moderate
review
Pathogenic
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.
Nonsense variant (p.Arg335Ter) in PHF6an established LoF disease gene for BFLSVariant in terminal exon (exon 11/11)
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
PP3
supporting
Pathogenic
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.
BayesDel score 0.83 (damaging prediction)SpliceAI max delta 0.07 (no splicing impact)
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data identified in any reviewed publication for NM_001015877.1:c.1003A>T.
PS3
No variant-specific functional assay for p.R335* was identified in the reviewed literature.
PS4
The variant is absent from ClinVar and no case reports were identified in the reviewed literature.
PM1
The variant lies in the C-terminal region (residue 335) of PHF6, outside the two characterized PHD finger domains.
PM6
No de novo event reported for this variant in the reviewed literature.
PP1
No cosegregation data available for this variant.
PP4
No patient phenotype data specific to this variant are available.
PP5
This variant is absent from ClinVar and has not been classified by any expert panel or reputable clinical source.
Benign
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%.
BS1
The variant is absent from gnomAD; allele frequency is 0%, below the BS1 threshold of 0.3%.
BS3
No variant-specific functional study demonstrates a benign or neutral effect for p.R335*.
BS4
No segregation data available to assess lack of cosegregation with disease.
BP4
BayesDel score of 0.83 predicts a damaging effect.
BP5
No observation of this variant in a case with an alternate molecular basis for disease.
N/A · 8
PS1 · PM5 · PP2 · BS2 · BP1 · BP2 · BP6 · 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
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.83.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
23791194 ↗
The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.
ONCOKB