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GNA11c.604C>TUncertain significance
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Variant interpretation report

GNA11 c.604C>T, p.(Arg202Trp)

NM_002067.5:c.604C>T NP_002058.2:p.(Arg202Trp) 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Supporting
PM1 · supporting

The variant p.Arg202Trp is located in the GTPase domain (switch I region) of GNA11 at the catalytic arginine residue (R202), which is essential for GTP hydrolysis. This is a well-characterized functional domain in G-alpha subunits, homologous to GNAQ R183 and GNAS R201. Mutation at this residue disrupts GTPase activity, leading to constitutive G-protein activation. The variant has been observed in COSMIC (COSV99030259, n=3 somatic occurrences), confirming its relevance in oncogenic contexts. However, cancerhotspots.org does not flag GNA11 R202 as statistically significant at the residue level, limiting strength to supporting.

PM2Supporting
PM2 · supporting

This variant is present in gnomAD v4.1 at an extremely low allele frequency (AF=3.10e-6, 5/1,612,672 alleles, 0 homozygotes), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada. The grpmax filtering allele frequency is 6.8e-7, further supporting rarity. However, because the variant is not completely absent (5 alleles detected), the strength is downgraded from moderate to supporting.

PP3Supporting
PP3 · supporting

REVEL score of 0.774 supports a deleterious effect on protein function. BayesDel score of 0.232 is equivocal and does not independently support or refute pathogenicity. SpliceAI predicts no significant splice impact (max delta 0.01). At least one line of computational evidence (REVEL) supports a deleterious effect, meeting PP3 at supporting level.

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: PM1 supporting, PM2 supporting, PP3 supporting; combination = 3 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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → 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
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99030259, n = 3 times).

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.

26 criteria with recorded statuses: 3 met · 17 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is not applicable: NM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a null variant.

PM1 (supporting): The variant is located at the catalytic arginine residue R202 in the GTPase switch I region of GNA11, a well-characterized functional domain essential for GTP hydrolysis. This residue is homologous to the canonical hotspot residues GNAQ R183 and GNAS R201. COSMIC confirms 3 somatic occurrences (COSV99030259).

PM2 (supporting): The variant is present in gnomAD v4.1 at an extremely low frequency (5/1,612,672 alleles, AF=3.10e-6, 0 homozygotes), well below the 0.1% threshold. It is absent from gnomAD v2.1 and gnomAD-Canada.

PP3 (supporting): REVEL predicts a deleterious effect (score 0.774). SpliceAI shows no splicing impact (max delta 0.01). BayesDel is equivocal (0.232).

All other assessed criteria are either not met (PS2, PS3, PS4, PM6, PP1, PP2, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP2, BP4, BP5, BP6) or not applicable (PVS1, PS1, PS5, PM5, BP1, BP7).

Combination: PM1 (supporting) + PM2 (supporting) + PP3 (supporting) = 3 supporting criteria. Under ACMG/AMP 2015 rules, 3 supporting criteria do not reach the threshold for Likely Pathogenic (requires ≥4 supporting, or ≥1 moderate + ≥2 supporting, or ≥2 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 3

PM1 SupportingThe variant p.Arg202Trp is located in the GTPase domain (switch I region) of GNA11 at the catalytic arginine residue (R202), which is essential for GTP hydrolysis. This is a well-characterized functional domain in G-alpha subunits, homologous to GNAQ R183 and GNAS R201. Mutation at this residue disrupts GTPase activity, leading to constitutive G-protein activation. The variant has been observed in COSMIC (COSV99030259, n=3 somatic occurrences), confirming its relevance in oncogenic contexts. However, cancerhotspots.org does not flag GNA11 R202 as statistically significant at the residue level, limiting strength to supporting. Details ▾Hide ▴
Evidence considered
  • Located at catalytic arginine R202 in GTPase switch I region
  • Well-characterized functional domain in G-alpha subunits
  • COSMIC COSV99030259: 3 somatic occurrences
  • Homologous to known hotspots GNAQ R183 and GNAS R201
  • cancerhotspots.org: residue not statistically significant for GNA11
Still missing
  • No residue-level hotspot statistical significance for GNA11 at cancerhotspots.org
Sources
oncokb ↗
PM2 SupportingThis variant is present in gnomAD v4.1 at an extremely low allele frequency (AF=3.10e-6, 5/1,612,672 alleles, 0 homozygotes), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada. The grpmax filtering allele frequency is 6.8e-7, further supporting rarity. However, because the variant is not completely absent (5 alleles detected), the strength is downgraded from moderate to supporting. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 5/1
  • 612
  • 672 alleles
  • AF=3.10e-6
  • 0 homozygotes
  • Absent from gnomAD v2.1
  • Absent from gnomAD-Canada v1.0
  • grpmax FAF=6.8e-7
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score of 0.774 supports a deleterious effect on protein function. BayesDel score of 0.232 is equivocal and does not independently support or refute pathogenicity. SpliceAI predicts no significant splice impact (max delta 0.01). At least one line of computational evidence (REVEL) supports a deleterious effect, meeting PP3 at supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.774 (damaging)
  • BayesDel: 0.232 (equivocal)
  • SpliceAI: max delta 0.01 (no splice impact)
Still missing
  • BayesDel score is equivocal
  • no HCI prior available for orthogonal in silico confirmation
Sources
revelbayesdelspliceai ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No publications or clinical reports documenting de novo occurrence were identified. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in literature or databases
Still missing
  • No parental testing or de novo confirmation data available
PS3 No variant-specific functional studies were identified. The literature search returned zero PMIDs for this variant, and OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. COSMIC reports 3 somatic occurrences, but these are observational, not experimental functional data. No publications testing NM_002067.5:c.604C>T or a systematically characterized range encompassing position 202 were found. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence
  • COSMIC: 3 somatic observations
  • not experimental functional data
  • No variant-specific functional studies in literature
Still missing
  • No experimental functional data for this variant or a systematically characterized range including R202
Sources
oncokb ↗
PS4 No case-control or prevalence data are available comparing this variant in affected versus unaffected individuals. The variant is absent from ClinVar, precluding any case-level enrichment analysis. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 5/1
  • 612
  • 672 alleles (AF 3.1e-6)
  • No case-control or odds-ratio data available
Still missing
  • No case-control study or affected-cohort enrichment analysis available
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM6 No de novo data are available for this variant. No publications or clinical reports documenting de novo occurrence with confirmed maternity/paternity were identified. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified
Still missing
  • No de novo testing data available
PP1 No co-segregation data are available for this variant. No family studies or pedigrees were identified in the literature or databases. Details ▾Hide ▴
Evidence considered
  • No co-segregation or family study data available
Still missing
  • No segregation analysis data available
PP2 Insufficient constraint data are available to assess whether GNA11 has a low rate of benign missense variation. No HCI prior probability, gnomAD missense z-score, or gene-level constraint metrics were available in the evidence files. While GNA11 is a highly conserved G-protein alpha subunit with specific activating missense mutations as the disease mechanism (gain-of-function at R202 and Q228), formal PP2 requires quantitative constraint data that are not present. Details ▾Hide ▴
Evidence considered
  • No HCI prior available (gene not supported)
  • No gnomAD constraint metrics available
  • GNA11 disease mechanism is gain-of-function via specific missense mutations
Still missing
  • Missing gnomAD missense constraint z-score or other gene-level missense depletion metrics
PP4 No phenotype or family history data are available for this proband. The variant's phenotype specificity cannot be assessed without clinical context. Details ▾Hide ▴
Evidence considered
  • No proband phenotype data provided
Still missing
  • Proband phenotype and family history not available for review
PP5 This variant is absent from ClinVar. No expert panel or reputable source classification is available to apply PP5. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no classification available
Sources
clinvar ↗
BA1 The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=3.10e-6
  • well below BA1 threshold of 1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The allele frequency in gnomAD v4.1 is 3.10e-6 (0.00031%), which is far below the 0.3% threshold for BS1. The highest subpopulation frequency is in European (Finnish) at 3.17e-5 (0.00317%), still well below 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF=3.10e-6
  • Finnish AF=3.17e-5
  • both well below BS1 threshold of 0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No homozygous observations of this variant are reported in gnomAD v2.1 or v4.1. The variant is present only in heterozygous state (5/1,612,672 alleles, 0 homozygotes). Details ▾Hide ▴
Evidence considered
  • 0 homozygotes in gnomAD v4.1
  • 0 homozygotes in gnomAD v2.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no deleterious effect were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no variant-specific functional studies were found in the literature. Details ▾Hide ▴
Evidence considered
  • No functional studies available
  • OncoKB: Unknown Oncogenic Effect
Still missing
  • No functional data demonstrating normal protein function
Sources
oncokb ↗
BS4 No segregation data are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No family studies or segregation analysis data
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No trans-phase data available
Still missing
  • No genotype phasing data
BP4 REVEL score of 0.774 supports a deleterious effect, contradicting the requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.232) is equivocal and SpliceAI (0.01) shows no splicing impact, but REVEL alone is sufficient to prevent BP4 from being met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.774 (supports damaging
  • contradicts BP4)
  • BayesDel: 0.232 (equivocal)
  • SpliceAI: max delta 0.01 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP5 No data are available regarding an alternative molecular basis for disease in this case. Details ▾Hide ▴
Evidence considered
  • No alternative molecular cause reported
Still missing
  • No information on other genetic findings in this case
BP6 This variant is absent from ClinVar; no benign or likely benign classification from a reputable source is available. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification available
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) does not apply to missense variants; variant bucket is 'other' with apply_generic_pvs1_framework set to false. Details ▾Hide ▴
Evidence considered
  • Missense variant p.Arg202Trp does not fall into PVS1 null-variant buckets
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant at codon 202 exists in ClinVar or the literature to serve as a comparator. The variant is entirely absent from ClinVar, and no different nucleotide change producing the same p.Arg202Trp amino acid change has been reported. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic comparator at this codon available
Sources
clinvar ↗
PM5 N/ANo pathogenic missense variants at the same residue (R202) have been identified in ClinVar. The PM5 candidate search was unable to confirm classic same-residue semantics; no comparator variants at this codon are available for assessment. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at GNA11 R202 in ClinVar
  • PM5 candidate harvesting returned 0 candidates
Sources
pm5_candidatesclinvar ↗
BP1 N/AGNA11 disease mechanism is gain-of-function through specific activating missense mutations (e.g., R202, Q228), not loss-of-function through truncating variants. BP1 applies only when truncating variants are the primary disease mechanism, making a missense variant less likely to be pathogenic. This premise does not hold for GNA11. Details ▾Hide ▴
Evidence considered
  • GNA11 disease mechanism is gain-of-function via specific missense activating mutations (R202
  • Q228)
  • Truncating variants are not the primary disease mechanism for GNA11-related disorders
BP7 N/ANM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous
PS5 N/AThis variant is absent from ClinVar; no expert panel or established reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no expert panel classification exists
Sources
clinvar ↗

Identifiers

Gene
GNA11
Transcript
NM_002067.5
Coding (HGVS c.)
NM_002067.5:c.604C>T
Protein (HGVS p.)
NP_002058.2:p.(Arg202Trp)
GRCh38
chr19:3115071 C>T
GRCh37
chr19:3115069 C>T
COSMIC
COSV99030259

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 5 / 1,612,672 alleles AF 3.1e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 3.1e-06 · 5 / 1,612,672 alleles · 0 hom · FAF 6.8e-07
European (Finnish)2 / 63,158 3.2e-05
European (non-Finnish)3 / 1,179,574 2.5e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 3.10044e-06; MAF= 0.00031%, 5/1612672 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.16666e-05; MAF= 0.00317%, 2/63158 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -72 bp
0.000
SpliceAI acceptor gainat -32 bp
0.000
SpliceAI donor lossat -257 bp
0.010
SpliceAI donor gainat +390 bp
0.010
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
0.774
BayesDel
0.232

How the predictions were used

PP3 SupportingREVEL score of 0.774 supports a deleterious effect on protein function. BayesDel score of 0.232 is equivocal and does not independently support or refute pathogenicity. SpliceAI predicts no significant splice impact (max delta 0.01). At least one line of computational evidence (REVEL) supports a deleterious effect, meeting PP3 at supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.774 (damaging)
  • BayesDel: 0.232 (equivocal)
  • SpliceAI: max delta 0.01 (no splice impact)
Still missing
  • BayesDel score is equivocal
  • no HCI prior available for orthogonal in silico confirmation
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.774 supports a deleterious effect, contradicting the requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.232) is equivocal and SpliceAI (0.01) shows no splicing impact, but REVEL alone is sufficient to prevent BP4 from being met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.774 (supports damaging
  • contradicts BP4)
  • BayesDel: 0.232 (equivocal)
  • SpliceAI: max delta 0.01 (no splice impact)
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_002067.5:c.604C>T is a missense variant (p.Arg202Trp), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.774. BayesDel score = 0.232155.

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 5 / 1,612,672 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 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

This variant is present in gnomAD v4.1 (AF= 3.10044e-06; MAF= 0.00031%, 5/1612672 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.16666e-05; MAF= 0.00317%, 2/63158 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

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 = 0.01). REVEL score = 0.774. BayesDel score = 0.232155.

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 previously been reported in somatic cancers (COSMIC; COSV99030259, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.