NM_002072.5:c.289C>T

GNAQ · NP_002063.2:p.(Leu97Phe) · NM_002072.5

GRCh37: chr9:80537109 G>A · GRCh38: chr9:77922193 G>A

Gene: GNAQ Transcript: NM_002072.5

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

GNAQ

Transcript

NM_002072.5

Protein

NP_002063.2:p.(Leu97Phe)

gnomAD AF

1.239498350227696e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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_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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence data is available for NM_002072.5:c.289C>T. No publications report this variant in a de novo context.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or prevalence data comparing affected versus unaffected individuals is available for this variant in GNAQ-associated disease.
PS5	Not met	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.	pm5_candidates clinvar
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	No data on observation in trans with a pathogenic GNAQ variant; trivially not applicable in the absence of any such data.
PM4	N/A	Variant is a missense substitution, not an in-frame deletion/insertion or stop-loss; PM4 applies only to protein-length-altering variants.
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not met	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.
PP1	Not met	No cosegregation data is available. No family studies report NM_002072.5:c.289C>T segregating with disease.
PP2	Not met	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.	oncokb
PP3	Met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data is available to assess whether the variant carrier's phenotype is highly specific for GNAQ-associated disease.
PP5	Not met	NM_002072.5:c.289C>T is absent from ClinVar. No reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	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.	gnomad_v4 gnomad_v2
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 1.24e-06 (0.000124%), far below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	No data on healthy adult carriers is available to assess whether this variant has been observed in a homozygous or hemizygous state without disease.
BS3	Not met	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.
BS4	Not met	No segregation data is available to demonstrate lack of cosegregation with disease in affected family members.
BP1	Not met	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.	oncokb
BP2	Not met	No data on observation in trans with a pathogenic variant is available for this variant.
BP3	N/A	Variant is a substitution; BP3 applies to in-frame deletions/insertions in non-repeat regions.
BP4	Not met	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.	revel bayesdel
BP5	Not met	No data is available indicating that this variant was observed in a case with an alternate molecular basis for disease.
BP6	Not met	NM_002072.5:c.289C>T is absent from ClinVar. No reputable source has classified this variant as benign.	clinvar
BP7	Not met	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.	spliceai

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