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LYFE SCIENCES
Project: HERA
NM_005188.3:c.1147A>G
p.Ile383Val  ·  CBL
ACMG/AMP
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Classification rationale
1

The CBL NM_005188.3:c.1147A>G (p.Ile383Val, p.I383V) variant has been reported in ClinVar as uncertain significance with two clinical laboratory submissions.

clinvar ↗
2

This variant is very rare in population databases, observed at 1/251292 alleles in gnomAD v2.1 and 3/1611950 alleles in gnomAD v4.1, and it was not observed in gnomAD-Canada v1.0.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
3

Available computational evidence is not sufficient for a directional computational criterion: REVEL is 0.605 and BayesDel is 0.0719745, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.8611e-06; MAF= 0.00019%, 3/1611950 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.334e-05; MAF= 0.00333%, 2/59988 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 4804130)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.605. BayesDel score = 0.0719745.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI383
Hotspots ↗