NM_001015877.1:c.1000G>T

PHF6 · NP_001015877.1:p.(Glu334Ter) · NM_001015877.1

GRCh37: chrX:133559262 G>T · GRCh38: chrX:134425232 G>T

Gene: PHF6 Transcript: NM_001015877.1

Final call

VUS

PM2_Supporting

Variant details

Gene

PHF6

Transcript

NM_001015877.1

Protein

NP_001015877.1:p.(Glu334Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: With PM2 at supporting strength only and no qualifying pathogenic or benign criterion combination meeting Likely Pathogenic, Pathogenic, Likely Benign, or Benign thresholds, the variant is classified as a Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not assessed	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework prefetch PMID:39405291
PS1	N/A	PS1 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.	clinvar
PS2	Not assessed	No confirmed de novo data with parental testing were identified, so this criterion cannot be assessed.
PS3	Not met	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.	oncokb PMID:12676923 PMID:23791194 PMID:27479181
PS4	Not assessed	No case-control or prevalence data showing enrichment of this variant in affected individuals were identified.	clinvar
PM1	Not met	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.	hotspots PMID:12676923 PMID:27479181
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.	prefetch
PM5	N/A	PM5 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.
PM6	Not assessed	No assumed de novo evidence without confirmed parental testing was identified.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is a missense-specific criterion and does not apply to this nonsense variant.	prefetch
PP3	N/A	PP3 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.	spliceai prefetch
PP4	Not assessed	No phenotype information was provided to determine whether the clinical presentation is highly specific for PHF6-related disease.
PP5	Not met	No reputable external pathogenic classification for this exact variant was identified in ClinVar, so PP5 is not supported.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals for whom a fully penetrant PHF6-related phenotype would be expected.
BS3	Not met	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.	PMID:12676923 PMID:23791194 PMID:27479181
BS4	Not assessed	No segregation data showing lack of cosegregation with disease were identified.
BP1	N/A	BP1 is a missense-specific criterion and does not apply to this nonsense variant.	prefetch
BP2	Not assessed	No phase information with another pathogenic variant was identified.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function. This variant is a nonsense substitution, so BP3 is not applicable.
BP4	N/A	BP4 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.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified for the relevant phenotype.
BP6	Not met	No reputable external benign classification for this exact variant was identified in ClinVar, so BP6 is not supported.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense substitution, so BP7 is not applicable.	spliceai prefetch

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.