About GNAQ
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GNAQ c.289C>T, p.(Leu97Phe)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate
NM_002072.5:c.289C>T is extremely rare in population databases. In gnomAD v4.1, the variant is observed at an allele frequency of 1.24e-06 (2/1,613,556 alleles, 0 homozygotes; grpmax FAF=4.43e-06), far below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
PP3Supporting
PP3 · supporting
In silico prediction tools support a deleterious effect. REVEL score is 0.748 (above the 0.5 threshold for damaging prediction). BayesDel score is 0.306, which is below commonly used damaging thresholds. SpliceAI predicts no splicing impact (max delta = 0.00). The REVEL score provides supporting-level evidence for pathogenicity.
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 moderate, PP3 supporting; combination = 1 moderate + 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,613,556 alleles
gnomAD v4.1: 2 / 1,613,556 alleles. Recorded AF 1.2395e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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. GNAQ, a G protein subunit, is recurrently mutated in uveal melanoma.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105143328, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 23 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002072.5:c.289C>T (p.Leu97Phe) is a missense variant in GNAQ, a G protein alpha subunit gene recurrently mutated in uveal melanoma.
This variant is extremely rare in population databases, observed in only 2 of 1,613,556 alleles in gnomAD v4.1 (allele frequency 1.24e-06), and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
In silico prediction tools provide supporting evidence for a deleterious effect; REVEL scores the variant at 0.748, above the damaging threshold. BayesDel score is 0.306, which is below commonly used thresholds. SpliceAI predicts no splicing impact.
The variant is absent from ClinVar and has not been reported in the literature as a germline variant. It has been observed in 2 somatic cancer samples in COSMIC (COSV105143328).
No functional studies, de novo reports, cosegregation data, or case-control data are available for this variant. Residue Leu97 is not within a known GNAQ mutational hotspot (canonical driver residues are Gln209 and Arg183).
The only applicable criteria are PM2 (moderate, based on extreme rarity in population databases) and PP3 (supporting, based on in silico prediction). No other pathogenic or benign criteria are met.
With only one moderate criterion (PM2) and one supporting criterion (PP3) met, the overall evidence is insufficient to classify this variant as pathogenic or likely pathogenic under ACMG/AMP 2015 rules. The classification is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateNM_002072.5:c.289C>T is extremely rare in population databases. In gnomAD v4.1, the variant is observed at an allele frequency of 1.24e-06 (2/1,613,556 alleles, 0 homozygotes; grpmax FAF=4.43e-06), far below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2/1
- 613
- 556 alleles (AF=1.24e-06
- grpmax FAF=4.43e-06). Absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Sources
PP3 SupportingIn silico prediction tools support a deleterious effect. REVEL score is 0.748 (above the 0.5 threshold for damaging prediction). BayesDel score is 0.306, which is below commonly used damaging thresholds. SpliceAI predicts no splicing impact (max delta = 0.00). The REVEL score provides supporting-level evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.748 (damaging). BayesDel=0.306 (borderline/low). SpliceAI max delta=0.00 (no splice impact).
Still missing
- HCI prior not available for GNAQ gene.
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No pathogenic variant with the same amino acid change (p.Leu97Phe) has been identified in ClinVar or the literature. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-amino-acid pathogenic comparator identified.
Still missing
- No literature data available for variant-specific PS1 assessment.
Sources
clinvar ↗pm5_candidates
PS2 No de novo occurrence data is available for NM_002072.5:c.289C>T. No publications report this variant in a de novo context. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or evidence sources.
Still missing
- No family-based or trio sequencing data available.
PS3 No variant-specific functional data exists for NM_002072.5:c.289C>T (p.Leu97Phe). OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. No experimental studies in the literature directly test this variant or a systematically characterized range that includes residue 97. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. COSMIC reports 2 somatic occurrences (COSV105143328) but no functional characterization.
Still missing
- No in vitro or in vivo functional studies identified for this variant. No saturation mutagenesis or systematic tiling screen covering residue 97.
Sources
PS4 No case-control or prevalence data comparing affected versus unaffected individuals is available for this variant in GNAQ-associated disease. Details ▾Hide ▴
Evidence considered
- No prevalence or case-control data identified.
Still missing
- No affected vs. control cohort data for GNAQ germline disease.
PM1 Residue Leu97 is not located within a well-characterized critical functional domain with established pathogenic missense constraint. It does not reside in a statistically significant mutational hotspot (cancerhotspots.org). The known GNAQ pathogenic hotspots (Gln209, Arg183) are distant from this residue. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. OncoKB: no variant-specific evidence. Known GNAQ driver residues (Q209
- R183) are remote from Leu97.
Still missing
- No functional domain characterization specific to the region around residue 97.
Sources
PM5 No pathogenic missense variant at the same residue (Leu97) with a different amino acid change was identified in ClinVar. The automated PM5 candidate search found zero same-residue comparator candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue candidates. ClinVar: absent for this variant and any L97 variants.
Still missing
- No ClinVar entries at residue 97 for GNAQ.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo reports exist for NM_002072.5:c.289C>T. No publications describe this variant in a de novo context with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No trio or de novo sequencing data for this variant.
PP1 No cosegregation data is available. No family studies report NM_002072.5:c.289C>T segregating with disease. Details ▾Hide ▴
Evidence considered
- No cosegregation or family-based evidence identified.
Still missing
- No family studies with this variant.
PP2 While GNAQ has known pathogenic missense variants (e.g., p.Gln209Leu/Pro, p.Arg183Gln/Cys), no gene-level missense constraint metrics (e.g., gnomAD missense Z-score, o/e ratio) are available in the evidence to determine whether GNAQ has a low rate of benign missense variation sufficient to meet PP2. Details ▾Hide ▴
Evidence considered
- GNAQ has established pathogenic missense hotspots (Q209
- R183) in somatic cancer. No gene-level constraint metrics available for PP2 evaluation.
Still missing
- No gnomAD missense constraint Z-score or o/e ratio retrieved. PP2 requires gene-level evidence of low benign missense variation.
Sources
PP4 No patient phenotype data is available to assess whether the variant carrier's phenotype is highly specific for GNAQ-associated disease. Details ▾Hide ▴
Evidence considered
- No phenotype data available for carrier.
Still missing
- No clinical phenotype information for the proband.
PP5 NM_002072.5:c.289C>T is absent from ClinVar. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
BA1 The variant allele frequency in gnomAD v4.1 is 1.24e-06 (0.000124%), far below the 1% BA1 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=1.24e-06
- well below 1% BA1 threshold.
Sources
BS1 The variant allele frequency in gnomAD v4.1 is 1.24e-06 (0.000124%), far below the 0.3% BS1 threshold. Details ▾Hide ▴
BS2 No data on healthy adult carriers is available to assess whether this variant has been observed in a homozygous or hemizygous state without disease. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available.
Still missing
- No homozygous or hemizygous carrier data.
BS3 No well-established functional studies demonstrate a benign effect for NM_002072.5:c.289C>T (p.Leu97Phe). No in vitro or in vivo data supports normal protein function for this variant. Details ▾Hide ▴
Evidence considered
- No benign functional data identified.
Still missing
- No functional studies demonstrating no deleterious effect.
BS4 No segregation data is available to demonstrate lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family or cosegregation data available.
Still missing
- No family-based non-segregation data.
BP1 GNAQ is known to harbor pathogenic missense variants (e.g., p.Gln209Leu, p.Arg183Gln) associated with uveal melanoma and other conditions. Disease is not exclusively caused by truncating variants, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- GNAQ has established pathogenic missense variants (Q209
- R183)
- disease mechanism is not limited to truncating variants.
Sources
BP2 No data on observation in trans with a pathogenic variant is available for this variant. Details ▾Hide ▴
Evidence considered
- No trans-phase data available.
Still missing
- No observation in trans with a known pathogenic GNAQ variant.
BP4 REVEL score of 0.748 is in the damaging range (>0.5), which does not support a benign in silico prediction. BayesDel 0.306 is borderline but does not independently meet a benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.748 (damaging
- not benign). BayesDel=0.306 (borderline
- not definitively benign).
Sources
revelbayesdel
BP5 No data is available indicating that this variant was observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause data available.
Still missing
- No observation in a case with a confirmed alternate genetic cause.
BP6 NM_002072.5:c.289C>T is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
BP7 NM_002072.5:c.289C>T is a missense variant (p.Leu97Phe), not a synonymous variant with no predicted splice impact. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. SpliceAI max delta=0.00
- but BP7 requires a synonymous variant.
Sources
PS5 No pathogenic missense variant at residue 97 has been identified in ClinVar; no same-residue comparator candidates were found. The residue is not within a statistically significant mutational hotspot per cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. PM5 candidate search: zero same-residue candidates found. ClinVar: absent.
Still missing
- No known pathogenic comparator at residue Leu97.
Sources
pm5_candidatesclinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002072.5:c.289C>T is a missense variant (p.Leu97Phe) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense substitution not eligible for PVS1 null-variant framework per PMC6185798.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo data on observation in trans with a pathogenic GNAQ variant; trivially not applicable in the absence of any such data. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a missense substitution, not an in-frame deletion/insertion or stop-loss; PM4 applies only to protein-length-altering variants. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a substitution; BP3 applies to in-frame deletions/insertions in non-repeat regions. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- GNAQ
- Transcript
- NM_002072.5
- Coding (HGVS c.)
- NM_002072.5:c.289C>T
- Protein (HGVS p.)
- NP_002063.2:p.(Leu97Phe)
- GRCh38
- chr9:77922193 G>A
- GRCh37
- chr9:80537109 G>A
- COSMIC
- COSV105143328
Gene diagram
Every interpreted variant in GNAQ, mapped onto the exon structure of NM_002072.5. Select a row to find it on the plot.
GNAQNM_002072.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GNAQ
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,613,556 alleles
AF 1.24e-06 · 0 homozygotes · FAF 4.43e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,556 alleles · 0 hom · FAF 4.4e-06
| African/African American2 / 74,956 | 2.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.2395e-06; MAF= 0.00012%, 2/1613556 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66823e-05; MAF= 0.00267%, 2/74956 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.748
- BayesDel
- 0.306
How the predictions were used
PP3 SupportingIn silico prediction tools support a deleterious effect. REVEL score is 0.748 (above the 0.5 threshold for damaging prediction). BayesDel score is 0.306, which is below commonly used damaging thresholds. SpliceAI predicts no splicing impact (max delta = 0.00). The REVEL score provides supporting-level evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL=0.748 (damaging). BayesDel=0.306 (borderline/low). SpliceAI max delta=0.00 (no splice impact).
Still missing
- HCI prior not available for GNAQ gene.
Sources
BP4 REVEL score of 0.748 is in the damaging range (>0.5), which does not support a benign in silico prediction. BayesDel 0.306 is borderline but does not independently meet a benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.748 (damaging
- not benign). BayesDel=0.306 (borderline
- not definitively benign).
Sources
revelbayesdel
BP7 NM_002072.5:c.289C>T is a missense variant (p.Leu97Phe), not a synonymous variant with no predicted splice impact. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. SpliceAI max delta=0.00
- but BP7 requires a synonymous variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.748. BayesDel score = 0.306198.
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
2 / 1,613,556 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002072.5%3Ac.289C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-80537109-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-77922193-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-77922193-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002072.5%3Ac.289C…
- OncoKB ↗www.oncokb.org/gene/GNAQ/L97F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121991110
- Cancer hotspots ↗www.cancerhotspots.org/
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= 1.2395e-06; MAF= 0.00012%, 2/1613556 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66823e-05; MAF= 0.00267%, 2/74956 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
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 = 0.00). REVEL score = 0.748. BayesDel score = 0.306198.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. GNAQ, 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; COSV105143328, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.