NM_001015877.1:c.823G>A

PHF6 · NP_001015877.1:p.(Gly275Arg) · NM_001015877.1

GRCh37: chrX:133549139 G>A · GRCh38: chrX:134415109 G>A

Gene: PHF6 Transcript: NM_001015877.1

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

PHF6

Transcript

NM_001015877.1

Protein

NP_001015877.1:p.(Gly275Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as 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	N/A	PVS1 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not met	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.	clinvar
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar pm5_candidates
PM1	Met	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.	gnomad_v2 gnomad_v4
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.	pm5_candidates
PM6	Not met	No assumed de novo occurrence was identified for this variant. The ClinVar submission reports maternal origin (SCV001142206), inconsistent with a de novo event.	clinvar
PP1	Not met	No cosegregation data are available for this variant in families with PHF6-related disorders (Börjeson-Forssman-Lehmann syndrome or hematologic malignancy predisposition).
PP2	Not assessed	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.
PP3	Not met	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.	bayesdel spliceai
PP4	Not met	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.	clinvar
PP5	Not met	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.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1, well below the BA1 allele frequency threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1, falling well below the non-VCEP BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease in affected families were available for this variant.
BP1	N/A	BP1 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.
BP2	N/A	BP2 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.
BP3	N/A	BP3 is not applicable. This variant is a single-nucleotide substitution, not an in-frame insertion/deletion in a repetitive region.
BP4	Not met	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.	bayesdel spliceai
BP5	Not met	No patient was identified in whom this variant was observed alongside a convincing alternate molecular basis for the phenotype.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 is not applicable. This variant is a single-nucleotide substitution, not a non-frameshift insertion/deletion or stop-loss variant.

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