Variant classification summary

NM_014159.6:c.4260del

SETD2 · NP_054878.5:p.(Glu1420AspfsTer12) · NM_014159.6

GRCh37: chr3:47161865 GC>G · GRCh38: chr3:47120375 GC>G

Gene: SETD2 Transcript: NM_014159.6

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Glu1420AspfsTer12)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift p.(Glu1420AspfsTer12) introduces a premature stop 12 residues downstream, predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): the deletion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

3

BP4 (Supporting): SpliceAI max delta 0.014 indicates no splice impact, but a single benign-supporting criterion does not override the pathogenic combination.

4

PVS1 (Very Strong) + PM2 (Supporting) = Likely Pathogenic under generic ACMG/AMP 2015 rules.

Final determination:

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 (Very Strong): the single-nucleotide deletion creates frameshift p.(Glu1420AspfsTer12), with a premature stop 12 residues downstream predicted to trigger nonsense-mediated decay.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework gnomad_v2 gnomad_v4 gnomad_canada
PS1	N/A	Not applicable: as a frameshift, the variant produces no altered amino acid to compare against a previously pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo occurrence was available.
PS3	Not assessed	Not assessed: no validated functional assay performed on this exact variant was available.
PS4	Not assessed	Not assessed: no case-control or variant-enrichment data were identified.	PMID:23417712 PMID:24509477 PMID:25728682
PM1	N/A	Not applicable: as a frameshift, the variant has no altered residue to evaluate for hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): the deletion is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no proband carrying a second pathogenic SETD2 variant in trans was observed.
PM4	N/A	Not applicable: the criterion evaluates protein length changes, and frameshifts do not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence without confirmed parentage was reported.
PP1	Not assessed	Not assessed: no family pedigree or segregation data were provided.
PP2	N/A	Not applicable: the criterion addresses missense variants, and this variant is a frameshift.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.014 is far below thresholds supporting a deleterious splice effect.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or diagnosis information was available.	pvs1_gene_context
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD, providing no allele frequency that could satisfy BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD, with no frequency exceeding a benign-population threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: absence from population sources provides no adult or homozygous observations.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data for this exact variant were available.
BS4	Not assessed	Not assessed: no non-segregation observations, unaffected carriers, or affected non-carriers were available.
BP1	N/A	Not applicable: the criterion addresses missense variants, and this variant is a frameshift.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans co-occurrence or inheritance data were available.
BP3	N/A	Not applicable: the criterion addresses in-frame changes in repetitive regions, not frameshifts.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.014 is well below the ~0.2 threshold for a splice-altering effect.	spliceai
BP5	Not assessed	Not assessed: no individual-level phenotype or alternative causal diagnosis was provided.
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: the criterion applies to synonymous variants; this frameshift alters the protein sequence.	generic_acmg_combination_rules

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