Variant classification summary

NM_001015877.1:c.903delinsGTTTCCT

PHF6 · NP_001015877.1:p.(Tyr301Ter) · NM_001015877.1

GRCh37: chrX:133551267 C>GTTTCCT · GRCh38: chrX:134417237 C>GTTTCCT

Gene: PHF6 Transcript: NM_001015877.1

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PHF6

Transcript

NM_001015877.1

Protein

NP_001015877.1:p.(Tyr301Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: p.(Tyr301Ter) is predicted to undergo nonsense-mediated decay in PHF6.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion supports a Likely Pathogenic classification.

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	Met	Met at very strong: p.(Tyr301Ter) lies 66 coding nucleotides before the final exon junction, supporting NMD in PHF6 under the generic SVI framework.	pvs1_generic_framework
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo observation is documented for PHF6 c.903delinsGTTTCCT.
PS3	Not assessed	Not assessed: no validated functional assay directly tested PHF6 c.903delinsGTTTCCT or p.(Tyr301Ter).
PS4	Not assessed	Not assessed: no exact-variant affected-case/control counts or enrichment statistic are available for PS4.	generic_acmg_combination_rules PMID:12676923 PMID:23791194 PMID:27479181
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, corresponding to allele frequency 0 versus the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, second-allele, or phase observation establishes the allelic configuration required for PM3 in this X-linked PHF6 case.	generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no unconfirmed de novo observation or parental-testing result is documented for PHF6 c.903delinsGTTTCCT.
PP1	Not assessed	Not assessed: no current-variant relatives, informative meioses, or phenotype-segregation data are documented for PHF6 c.903delinsGTTTCCT.	PMID:12676923
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is a nonsense change predicted to produce p.(Tyr301Ter), outside PP3's calibrated missense and splice-region/intronic scope.
PP4	Not assessed	Not assessed: no patient phenotype, diagnosis, or family history is provided to establish a highly specific PHF6 disease match.	generic_acmg_combination_rules PMID:12676923 PMID:23791194 PMID:27479181
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.903delinsGTTTCCT.	clinvar oncokb
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the generic BA1 allele-frequency threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, so the variant does not reach the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no unaffected carrier or hemizygote observation is documented, and gnomAD v2.1 and v4.1 report the variant as absent.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay demonstrated preserved PHF6 function for c.903delinsGTTTCCT or p.(Tyr301Ter).
BS4	Not assessed	Not assessed: no tested unaffected carriers or other informative relatives are documented for PHF6 c.903delinsGTTTCCT.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no informative individual has documented phase showing this variant in trans or cis with another pathogenic variant for BP2.	generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is a nonsense change predicted to produce p.(Tyr301Ter), outside BP4's calibrated missense and splice-region/intronic scope.
BP5	Not assessed	Not assessed: no affected individual with an alternative molecular explanation is documented for this exact variant.	generic_acmg_combination_rules PMID:12676923 PMID:23791194 PMID:27479181
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion for c.903delinsGTTTCCT.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001015877.1:c.903delinsGTTTCCT in PHF6 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001015877.1:p.(Tyr301Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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.