Variant classification summary

NM_152756.4:c.3667G>T

RICTOR · NP_689969.2:p.(Asp1223Tyr) · NM_152756.4

GRCh37: chr5:38950283 C>A · GRCh38: chr5:38950181 C>A

Gene: RICTOR Transcript: NM_152756.4

Final call

VUS

PM2 supporting

Variant details

Gene

RICTOR

Transcript

NM_152756.4

Protein

NP_689969.2:p.(Asp1223Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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.

4

No variant-specific functional studies, segregation data, de novo reports, or case-control data are available. OncoKB reports Unknown Oncogenic Effect.

5

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).

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_152756.4:c.3667G>T is a missense substitution (p.Asp1223Tyr). It does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice variants) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	No known pathogenic variant with the same amino acid change (p.Asp1223Tyr) has been identified in ClinVar or the literature. No comparator exists for PS1 assessment.	clinvar
PS2	Not assessed	No de novo data (with or without confirmed parentage) are available for NM_152756.4:c.3667G>T.
PS3	Not met	No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data comparing affected individuals to controls are available for this variant.
PS5	N/A	No established pathogenic missense variant at the same amino acid residue (Asp1223) has been identified to serve as a comparator. PM5 candidate search returned zero candidates.	pm5_candidates
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per CancerHotspots.org, nor in a well-established functional domain without benign variation.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variants have been identified at the same amino acid residue (Asp1223) in ClinVar. PM5 candidate harvesting returned zero candidates at this residue.	pm5_candidates clinvar
PM6	Not assessed	No de novo data (with or without confirmed parentage) are available for NM_152756.4:c.3667G>T.
PP1	Not assessed	No co-segregation data are available for this variant; no family studies have reported NM_152756.4:c.3667G>T.
PP2	Not assessed	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	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.471 (below the typical pathogenic threshold of 0.5 for supporting evidence). BayesDel score is 0.102. SpliceAI predicts no significant splice impact (max delta score 0.05).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype data are available to assess whether the clinical presentation is highly specific for a RICTOR-associated disease.
PP5	Not met	NM_152756.4:c.3667G>T is absent from ClinVar; no reputable source has reported this variant as pathogenic. OncoKB classifies this variant as 'Unknown Oncogenic Effect.'	clinvar oncokb
BA1	Not met	NM_152756.4:c.3667G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0, which does not meet the BA1 threshold (>1% for non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_152756.4:c.3667G>T is absent from gnomAD. The allele frequency is 0, which does not meet the BS1 threshold (>0.3% for non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available on observation of this variant in healthy adults for a disorder expected to be fully penetrant.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease.
BP1	Not met	Although literature suggests RICTOR loss of function may contribute to germline disease, the gene-disease relationship is preliminary (literature_only, no established inheritance pattern). Truncating variants have not been definitively established as the primary disease mechanism for RICTOR. BP1 cannot be applied.	pvs1_gene_context
BP2	N/A	No observation of this variant in trans with a pathogenic variant. BP2 requires observation in trans with a known pathogenic dominant variant or for recessive disorders; neither condition is established for RICTOR.
BP3	N/A	In-frame deletions/insertions in repetitive regions without known function. NM_152756.4:c.3667G>T is a missense substitution, not an in-frame indel.
BP4	Not met	Multiple lines of computational evidence do not consistently predict no impact on the gene product. REVEL score is 0.471 (intermediate, not clearly benign), BayesDel is 0.102 (low but not definitively benign), and SpliceAI predicts no splice impact. The evidence is mixed and does not meet the threshold for BP4.	revel bayesdel spliceai
BP5	Not assessed	No data are available on an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	No reputable source has reported NM_152756.4:c.3667G>T as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_152756.4:c.3667G>T is a missense variant (p.Asp1223Tyr), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact.
PM3	N/A	PM3 requires observation of the variant in trans with a pathogenic variant for recessive disorders. RICTOR has no established recessive disease association, and no phase data are available.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_152756.4:c.3667G>T is a missense substitution.

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