0%
GNA11c.506_507delinsTTUncertain significance
Print report
Variant interpretation report

GNA11 c.506_507delinsTT, p.(Thr169Ile)

NM_002067.5:c.506_507delinsTT NP_002058.2:p.(Thr169Ile) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About GNA11

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 1 met · 6 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 1

PM2 SupportingNM_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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PM1 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. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: not significant. COSMIC: variant not reported. Known GNA11 hotspots (Q209
  • R183) are at different residues.
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no splice impact).
  • REVEL: not available (not a single nucleotide substitution).
  • BayesDel: not available (not a single nucleotide substitution).
Sources
spliceai ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). BA1 requires an allele frequency exceeding 1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 across all gnomAD datasets
  • does not exceed 1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 across all gnomAD datasets
  • does not exceed 0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 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. Details ▾Hide ▴
Evidence considered
  • GNA11 disease mechanism is primarily gain-of-function via missense variants.
Sources
pvs1_gene_context
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no splice impact).
  • REVEL/BayesDel: not available for delins variants.
Sources
spliceai ↗

Not assessed · 15 · no assessment recorded

PS2 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. Details ▾Hide ▴
Still missing
  • No parental testing or de novo report in the literature.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with no case reports.
Still missing
  • No case-control or case-series data available.
Sources
clinvar ↗
PM6 No de novo data are available for this variant. PM6 requires observation of a de novo occurrence without confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • No de novo reports available.
PP1 No segregation data are available for NM_002067.5:c.506_507delinsTT. Details ▾Hide ▴
Still missing
  • No family segregation data.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported
  • no probability score available.
Still missing
  • No HCI prior score for GNA11.
PP4 No patient phenotype or family history data are available to assess specificity for GNA11-associated disease. Details ▾Hide ▴
Still missing
  • No clinical phenotype data provided.
PP5 NM_002067.5:c.506_507delinsTT is absent from ClinVar. No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries
  • no classification by any submitter.
Still missing
  • No reputable source classification available.
Sources
clinvar ↗
BS2 No data are available regarding observation of this variant in a homozygous state or in trans with a pathogenic variant in healthy adults. Details ▾Hide ▴
Still missing
  • No data on homozygous or trans observations in healthy controls.
BS3 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. Details ▾Hide ▴
Still missing
  • No functional studies evaluating this variant.
BS4 No segregation data are available. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic GNA11 variant. Details ▾Hide ▴
Still missing
  • No trans-phase observation data.
BP5 No data are available regarding observation of this variant in a case where an alternative molecular basis for disease has been identified. Details ▾Hide ▴
Still missing
  • No data on alternative molecular findings in cases with this variant.
BP6 NM_002067.5:c.506_507delinsTT is absent from ClinVar. No reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries
  • no classification by any submitter.
Still missing
  • No reputable source classification available.
Sources
clinvar ↗
PS5 No case-control studies with statistically significant disease association are available for NM_002067.5:c.506_507delinsTT. Details ▾Hide ▴
Still missing
  • No case-control studies evaluating this variant.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • In-frame delins produces missense p.Thr169Ile
  • not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/AExcluded per adjudication directive (indel variant; PM3 not assessed). Details ▾Hide ▴

No further detail was recorded.

PM4 N/AAlthough 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. Details ▾Hide ▴
Evidence considered
  • Protein: p.Thr169Ile — single residue substitution
  • protein length unchanged.
Sources
pvs1_variant_assessment
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 candidates at codon 169.
Sources
pm5_candidates
BP3 N/ANM_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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_002067.5:c.506_507delinsTT encodes p.Thr169Ile, a missense change. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • p.Thr169Ile is a missense change
  • not synonymous.

Identifiers

Gene
GNA11
Transcript
NM_002067.5
Coding (HGVS c.)
NM_002067.5:c.506_507delinsTT
Protein (HGVS p.)
NP_002058.2:p.(Thr169Ile)
GRCh38
chr19:3114973 CC>TT
GRCh37
chr19:3114971 CC>TT

Gene diagram

Every interpreted variant in GNA11, mapped onto the exon structure of NM_002067.5. Select a row to find it on the plot.

GNA11NM_002067.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -29 bp
0.010
SpliceAI acceptor gainat +26 bp
0.020
SpliceAI donor lossat -159 bp
0.010
SpliceAI donor gainat +488 bp
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no splice impact).
  • REVEL: not available (not a single nucleotide substitution).
  • BayesDel: not available (not a single nucleotide substitution).
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta = 0.02 (no splice impact).
  • REVEL/BayesDel: not available for delins variants.
Sources
spliceai ↗
BP7 N/ANM_002067.5:c.506_507delinsTT encodes p.Thr169Ile, a missense change. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • p.Thr169Ile is a missense change
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.