NM_152756.4:c.3667G>T (p.Asp1223Tyr) is a missense variant in RICTOR. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).1 This variant is absent from ClinVar; no reputable source has classified it as pathogenic or benign. It is absent from COSMIC and does not lie in a statistically significant mutational hotspot.2 Computational predictors are equivocal: REVEL score is 0.471 (intermediate, below the typical 0.5 pathogenicity threshold), BayesDel is 0.102, and SpliceAI predicts no significant splice impact (max delta 0.05). These do not meet PP3 or BP4 thresholds.3 No variant-specific functional studies, segregation data, de novo reports, or case-control data are available. OncoKB reports Unknown Oncogenic Effect.4 Only one criterion is met: PM2 (supporting). Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), a single supporting criterion is insufficient to classify this variant as likely pathogenic or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS).5
RICTOR
Final classification
VUS
RICTOR c.3667G>T · p.Asp1223Tyr
RICTOR
NM_152756.4:c.3667G>T (p.Asp1223Tyr) is a missense variant in RICTOR. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).
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.
Classification rationale
PM2
VUS
RICTOR c.3667G>T
PM2
→
VUS
Gene diagram
· NM_152756.4 · variants mapped to exon structure
RICTOR
NM_152756.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 19 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_152756.4:c.3667G>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), consistent with a rare variant absent from general population controls.
Absent from gnomAD v2.1 (AC=nullAN=null).Absent from gnomAD v4.1 (AC=null
Assessed · not applied
Pathogenic
PS2
No de novo data (with or without confirmed parentage) are available for NM_152756.4:c.3667G>T.
PS3
No well-established functional studies demonstrating a damaging effect have been identified for this variant.
PS4
No case-control or prevalence data comparing affected individuals to controls are available for this variant.
PM1
This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org, nor in a well-established functional domain without benign variation.
PM6
No de novo data (with or without confirmed parentage) are available for NM_152756.4:c.3667G>T.
PP1
No co-segregation data are available for this variant; no family studies have reported NM_152756.4:c.3667G>T.
PP2
HCI prior probability data are not available for RICTOR; cannot assess whether the gene has a low rate of benign missense variation relative to pathogenic missense variation.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient phenotype data are available to assess whether the clinical presentation is highly specific for a RICTOR-associated disease.
PP5
NM_152756.4:c.3667G>T is absent from ClinVar; no reputable source has reported this variant as pathogenic.
Benign
BA1
NM_152756.4:c.3667G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_152756.4:c.3667G>T is absent from gnomAD.
BS2
No data are available on observation of this variant in healthy adults for a disorder expected to be fully penetrant.
BS3
No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP1
Although literature suggests RICTOR loss of function may contribute to germline disease, the gene-disease relationship is preliminary (literature_only, no established inheritance pattern).
BP4
Multiple lines of computational evidence do not consistently predict no impact on the gene product.
BP5
No data are available on an alternate molecular basis for disease in a case harboring this variant.
BP6
No reputable source has reported NM_152756.4:c.3667G>T as benign.
N/A · 8
PVS1 · PS1 · PM3 · PM4 · PM5 · BP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.471. BayesDel score = 0.102236.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RICTOR, a core component of the oncogenic mTOR2 complex, is altered by amplification or mutation in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links