NM_002067.5:c.506_507delinsTT

GNA11 · NP_002058.2:p.(Thr169Ile) · NM_002067.5

GRCh37: chr19:3114971 CC>TT · GRCh38: chr19:3114973 CC>TT

Gene: GNA11 Transcript: NM_002067.5

Final call

VUS

PM2 supporting

Variant details

Gene

GNA11

Transcript

NM_002067.5

Protein

NP_002058.2:p.(Thr169Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002067.5:c.506_507delinsTT (p.Thr169Ile) in GNA11 is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting.

The variant is not a null variant (nonsense, frameshift, or canonical splice site) and does not qualify for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798); it is an in-frame delins producing a single missense substitution.

No additional pathogenic or benign criteria are met. Computational evidence (SpliceAI max delta = 0.02) does not support PP3 or BP4, and no functional, segregation, or case-level data are available. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules; PM2_Supporting alone is insufficient to reach Likely Pathogenic or Likely Benign.

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	NM_002067.5:c.506_507delinsTT is an in-frame deletion-insertion producing a single missense substitution (p.Thr169Ile). It does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). The PVS1 variant assessment confirms apply_generic_pvs1_framework is false.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No alternative nucleotide change producing the same amino acid substitution (p.Thr169Ile) has been identified as pathogenic at this codon. PS1 requires a known pathogenic missense at the same residue arising from a different nucleotide change.
PS2	Not assessed	No de novo data are available for NM_002067.5:c.506_507delinsTT. PS2 requires demonstration of a de novo occurrence with confirmed maternity and paternity.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified for NM_002067.5:c.506_507delinsTT (p.Thr169Ile). OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no variant-specific functional PMIDs were retrieved.	oncokb
PS4	Not assessed	No case-control data comparing variant prevalence in affected versus unaffected individuals are available. The variant is absent from ClinVar and no case reports have been identified.	clinvar
PS5	Not assessed	No case-control studies with statistically significant disease association are available for NM_002067.5:c.506_507delinsTT.
PM1	Not met	p.Thr169Ile is not located in a statistically significant mutational hotspot. While residue 169 lies within the G-alpha GTPase domain of GNA11, no ClinGen-specified critical functional domain has been established for this gene, and hotspot analysis confirms the variant is not in a recurrently mutated region. Canonical activating GNA11 hotspots (e.g., Q209, R183) localize elsewhere.
PM2	Met	NM_002067.5:c.506_507delinsTT is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0), meeting the PM2 threshold for absence from population controls (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Excluded per adjudication directive (indel variant; PM3 not assessed).
PM4	N/A	Although NM_002067.5:c.506_507delinsTT is a deletion-insertion at the nucleotide level, the protein product is a single amino acid substitution (p.Thr169Ile) with no change in protein length (359 wild-type residues, 359 variant residues). PM4 requires in-frame deletions/insertions that alter protein length or stop-loss variants.	pvs1_variant_assessment
PM5	N/A	No same-residue pathogenic comparator variants at codon 169 were identified. The PM5 candidate search returned zero ClinVar candidates, and classic PM5 semantics cannot be confirmed for this delins variant.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. PM6 requires observation of a de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	No segregation data are available for NM_002067.5:c.506_507delinsTT.
PP2	Not assessed	HCI prior score is not available for GNA11; cannot assess whether GNA11 has a low rate of benign missense variation. PP2 is not independently assessable without this data.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel are not available for this variant type (delins). No multiple lines of computational evidence support a deleterious effect. PP3 requires multiple lines of computational evidence in favor of pathogenicity.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess specificity for GNA11-associated disease.
PP5	Not assessed	NM_002067.5:c.506_507delinsTT is absent from ClinVar. No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). BA1 requires an allele frequency exceeding 1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). BS1 requires an allele frequency exceeding 0.3% in population controls.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in a homozygous state or in trans with a pathogenic variant in healthy adults.
BS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified that demonstrate no deleterious effect for NM_002067.5:c.506_507delinsTT.
BS4	Not assessed	No segregation data are available. BS4 requires lack of segregation with disease in affected family members.
BP1	Not met	GNA11-associated disease is primarily driven by missense gain-of-function variants (e.g., Q209L, Q209P, R183C) in uveal melanoma and vascular malformations, not by truncating variants. BP1 applies only when a missense variant occurs in a gene where truncating variants are the primary known disease mechanism.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic GNA11 variant.
BP3	N/A	NM_002067.5:c.506_507delinsTT is not located within a repetitive region. BP3 applies only to in-frame deletions or insertions in regions with a known repetitive sequence.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.02). However, only a single line of computational evidence is available (SpliceAI); REVEL and BayesDel are not applicable to this variant type. BP4 requires multiple lines of computational evidence suggesting no impact, which cannot be met with SpliceAI alone.	spliceai
BP5	Not assessed	No data are available regarding observation of this variant in a case where an alternative molecular basis for disease has been identified.
BP6	Not assessed	NM_002067.5:c.506_507delinsTT is absent from ClinVar. No reputable source has reported this variant as benign.	clinvar
BP7	N/A	NM_002067.5:c.506_507delinsTT encodes p.Thr169Ile, a missense change. BP7 applies only to synonymous variants with no predicted splice impact.

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