About CBL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CBL c.1147A>C, p.(Ile383Leu)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
This variant is located in the CBL RING finger domain (residues 381-420), a critical and well-established functional domain. Missense variants in this domain are a known disease mechanism for CBL-related disorders (Noonan-like syndrome/CBL syndrome), which has a recognized germline disease association. UniProt confirms residue 383 lies within the RING-type zinc finger domain.
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 3.98x10^-6 (1/251,292 alleles, 0 homozygotes), and in gnomAD v4.1 at 6.20x10^-7 (1/1,612,068 alleles, 0 homozygotes). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0.
PP3Supporting
PP3 · supporting
REVEL predicts a deleterious effect with a score of 0.786, which is above the established pathogenic threshold (>0.5). However, BayesDel (0.134) is discordant and does not support pathogenicity. SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence is mixed but the REVEL meta-predictor strongly supports a damaging effect.
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: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 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
1 / 1,612,068 alleles
gnomAD v4.1: 1 / 1,612,068 alleles. Recorded AF 6.20321e-07. Recorded homozygote count 0.
gnomAD v2.1
This 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).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
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. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
26 criteria with recorded statuses: 3 met · 13 not met · 6 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_005188.3:c.1147A>C (p.Ile383Leu) is a missense variant in exon 8 of the CBL gene.
This variant is located in the CBL RING finger domain (residues 381-420), a critical functional domain where missense variants are an established disease mechanism for Noonan-like syndrome/CBL syndrome (PM1).
It is extremely rare in population databases: observed in 1 of 251,292 alleles in gnomAD v2.1 (AF=3.98x10^-6) and 1 of 1,612,068 alleles in gnomAD v4.1 (AF=6.20x10^-7), with no homozygotes in any population dataset, meeting PM2 criteria.
In silico analysis with REVEL (score 0.786) predicts a deleterious effect, though BayesDel (0.134) is discordant (PP3).
SpliceAI predicts no splice impact (max delta = 0.00).
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae, SCV002596392). No expert panel review is available.
No functional studies, segregation data, case-control analyses, or de novo observations have been reported for this variant in the literature.
OncoKB classifies this variant as having Unknown Oncogenic Effect.
The variant has not been reported in COSMIC and does not lie in a statistically significant cancer hotspot.
Overall, applying generic ACMG/AMP 2015 criteria, the evidence is limited to PM1 (moderate) + PM2 (supporting) + PP3 (supporting). No benign criteria are met. This is insufficient to reach a likely pathogenic classification (requires at least 2 moderate or 1 strong). The variant remains a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 ModerateThis variant is located in the CBL RING finger domain (residues 381-420), a critical and well-established functional domain. Missense variants in this domain are a known disease mechanism for CBL-related disorders (Noonan-like syndrome/CBL syndrome), which has a recognized germline disease association. UniProt confirms residue 383 lies within the RING-type zinc finger domain. Details ▾Hide ▴
Evidence considered
- Located in CBL RING finger domain (residues 381-420)
- RING domain is a critical functional domain with established pathogenic missense variants
- Germline CBL disease context supported by literature (PMID:25952305)
Sources
pvs1_gene_context
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 3.98x10^-6 (1/251,292 alleles, 0 homozygotes), and in gnomAD v4.1 at 6.20x10^-7 (1/1,612,068 alleles, 0 homozygotes). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 3.98e-06 (<0.1%)
- gnomAD v4.1 AF = 6.20e-07 (<0.1%)
- Absent from gnomAD-Canada
- 0 homozygotes in all datasets
Sources
PP3 SupportingREVEL predicts a deleterious effect with a score of 0.786, which is above the established pathogenic threshold (>0.5). However, BayesDel (0.134) is discordant and does not support pathogenicity. SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence is mixed but the REVEL meta-predictor strongly supports a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL = 0.786 (deleterious)
- BayesDel = 0.134 (benign-leaning)
- SpliceAI max delta = 0.00
Still missing
- Discordance between REVEL and BayesDel weakens confidence
Sources
Not met · 13 · evaluated, threshold not reached
PS2 No de novo occurrence of NM_005188.3:c.1147A>C has been reported in the literature or in ClinVar. Exploratory literature search found no studies documenting de novo status for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or PubMed
Still missing
- No de novo segregation data available
Sources
PS3 No well-established functional studies demonstrate a damaging effect for this exact variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' The variant resides in the CBL RING finger domain, a known functional domain, but direct experimental evidence (e.g., ubiquitin ligase activity, signaling assays) for p.Ile383Leu is absent from the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- No variant-specific functional assays identified
Still missing
- No functional studies for p.Ile383Leu
- No high-throughput functional data including this variant
Sources
PS4 No case-control data or statistically significant enrichment in affected individuals versus controls is available. The variant is present in only 1 of 251,292 alleles in gnomAD v2.1 and 1 of 1,612,068 alleles in gnomAD v4.1. A single ClinVar submission (Labcorp/Invitae) classifies it as Uncertain significance without aggregate case counts. The variant prevalence in affected populations is not established. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 292 alleles
- gnomAD v4.1: 1/1
- 612
- 068 alleles
- ClinVar: 1 submission
- VUS
- no case-control data
Still missing
- No case-control studies
- No odds ratio or enrichment statistics
Sources
PM6 No assumed de novo observations have been reported for this variant. Exploratory literature search found no cases of de novo occurrence without confirmed parentage. PM6 cannot be applied without at least one reported de novo event. Details ▾Hide ▴
Evidence considered
- No de novo reports in literature or ClinVar
Still missing
- No de novo observations of any kind
PP1 No segregation data are available for this variant. No family studies demonstrating cosegregation of NM_005188.3:c.1147A>C with disease in multiple affected family members have been published. Details ▾Hide ▴
Evidence considered
- No familial segregation studies identified
Still missing
- No family-based segregation data
PP5 No reputable source reports this variant as pathogenic. The sole ClinVar submission (Labcorp/Invitae, SCV002596392) classifies it as Uncertain significance. The only PMID cited by that submission (28492532) is a methodology paper describing the Sherloc classification framework and does not mention this specific variant. No other source asserts pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS (1 submitter)
- No source reports variant as pathogenic
Sources
clinvar ↗28492532
BA1 BA1 requires an allele frequency >1% in population databases. This variant has an allele frequency of 3.98x10^-6 in gnomAD v2.1 and 6.20x10^-7 in gnomAD v4.1, both far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 3.98e-06 (<<1%)
- gnomAD v4.1 AF = 6.20e-07 (<<1%)
Sources
BS1 BS1 requires an allele frequency >0.3% in population databases. This variant is observed at 3.98x10^-6 (v2.1) and 6.20x10^-7 (v4.1), far below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 3.98e-06 (<<0.3%)
- gnomAD v4.1 AF = 6.20e-07 (<<0.3%)
Sources
BS3 No well-established functional studies demonstrate a neutral or benign effect for this variant. Exploratory search found no in vitro or in vivo functional assays showing no damaging effect for p.Ile383Leu. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign effect
Still missing
- No functional data of any kind for this variant
Sources
BS4 BS4 requires lack of segregation in affected family members. No family segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies to evaluate segregation
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. REVEL strongly predicts a deleterious effect (0.786), which contradicts benign interpretation. Although BayesDel (0.134) and SpliceAI (0.00) are neutral, the REVEL score alone precludes application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL = 0.786 (deleterious
- precludes BP4)
- BayesDel = 0.134
- SpliceAI max delta = 0.00
Sources
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such evidence is available for this variant. Details ▾Hide ▴
Evidence considered
- No evidence of alternate molecular diagnosis in a carrier
Still missing
- No case data available
BP6 No reputable source reports this variant as benign. The sole ClinVar submission classifies it as Uncertain significance. No expert panel or clinical laboratory has asserted a benign classification. Details ▾Hide ▴
Not assessed · 6 · no assessment recorded
PS1 No evidence of a different nucleotide change at codon 383 (c.1147) predicting the same missense change (p.Ile383Leu) with an established pathogenic classification. No such variant was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change at c.1147 predicting p.Ile383Leu found in ClinVar
Still missing
- No known pathogenic variant at the same codon with a different nucleotide change
Sources
PM5 PM5 candidate harvesting found no same-residue comparator variants for residue 383. No different missense change at this residue with an established pathogenic classification was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator candidates identified
Still missing
- No pathogenic missense variant at the same residue for comparison
Sources
pm5_candidatesclinvar ↗
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While CBL-related disorders are indeed caused by missense variants (gain-of-function mechanism in the RING domain), gene-level constraint metrics (e.g., missense Z-score, o/e ratio) are not available in the evidence set to assess the rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- CBL missense variants are a known disease mechanism
- No gene constraint metrics available
Still missing
- Missense constraint metrics (Z-score
- o/e) needed to assess benign missense variation rate
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient-specific phenotype information is available for this case. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available
Still missing
- Patient phenotype and family history not provided
BS2 While the variant is observed in 1 heterozygous individual in each of gnomAD v2.1 and v4.1 (which are general population databases), the phenotype of these individuals is unknown. CBL-related disorders (Noonan-like syndrome/CBL syndrome) can exhibit variable expressivity and incomplete penetrance, so observation in a population database does not exclude pathogenicity. Without phenotype confirmation, BS2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- Variant observed in 1 heterozygote in gnomAD v2.1 and v4.1
- Phenotype of gnomAD individuals unknown
- CBL disorders have variable expressivity
Still missing
- Phenotype status of gnomAD carriers unknown
Sources
PS5 PS5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously observed. No pathogenic missense variant at residue 383 was identified in the evidence set. PM5 candidate harvesting found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- No pathogenic missense comparator at residue 383 (Ile)
Still missing
- No established pathogenic variant at residue 383
Sources
pm5_candidates
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to this missense variant (p.Ile383Leu). The variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus variants, and no evidence of aberrant splicing leading to nonsense-mediated decay has been identified (SpliceAI max delta = 0.00). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- SpliceAI max delta score = 0.00
- Categorized as 'other' bucket by PVS1 variant assessment
Sources
BP1 N/ABP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. CBL-related disorders are primarily caused by gain-of-function missense variants in the RING finger and linker domains, not by truncating loss-of-function variants. Therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- CBL disease mechanism is gain-of-function missense
- not truncating LoF
Sources
pvs1_gene_context
BP2 N/ABP2 applies when a variant is observed in trans with a pathogenic variant in a recessive disorder. CBL-related disorders are autosomal dominant (Noonan-like syndrome/CBL syndrome), not recessive. BP2 is not applicable. Details ▾Hide ▴
Evidence considered
- CBL-related disorders are autosomal dominant
- Not a recessive disease gene
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_005188.3:c.1147A>C is a missense variant (p.Ile383Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Identifiers
- Gene
- CBL
- Transcript
- NM_005188.3
- Coding (HGVS c.)
- NM_005188.3:c.1147A>C
- Protein (HGVS p.)
- NP_005179.2:p.(Ile383Leu)
- GRCh38
- chr11:119278217 A>C
- GRCh37
- chr11:119148927 A>C
- ClinVar
- 1716702
Gene diagram
Every interpreted variant in CBL, mapped onto the exon structure of NM_005188.3. Select a row to find it on the plot.
CBLNM_005188.3
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 CBL
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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
1 / 1,612,068 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,292 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,612,068 alleles · 0 hom
| Admixed American1 / 60,008 | 1.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,292 alleles · 0 hom
| Admixed American1 / 34,588 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20321e-07; MAF= 0.00006%, 1/1612068 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66644e-05; MAF= 0.00167%, 1/60008 alleles, homozygotes = 0).
gnomAD v2.1
This 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).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.786
- BayesDel
- 0.134
How the predictions were used
PP3 SupportingREVEL predicts a deleterious effect with a score of 0.786, which is above the established pathogenic threshold (>0.5). However, BayesDel (0.134) is discordant and does not support pathogenicity. SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence is mixed but the REVEL meta-predictor strongly supports a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL = 0.786 (deleterious)
- BayesDel = 0.134 (benign-leaning)
- SpliceAI max delta = 0.00
Still missing
- Discordance between REVEL and BayesDel weakens confidence
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. REVEL strongly predicts a deleterious effect (0.786), which contradicts benign interpretation. Although BayesDel (0.134) and SpliceAI (0.00) are neutral, the REVEL score alone precludes application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL = 0.786 (deleterious
- precludes BP4)
- BayesDel = 0.134
- SpliceAI max delta = 0.00
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_005188.3:c.1147A>C is a missense variant (p.Ile383Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.786. BayesDel score = 0.134053.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,612,068 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
1 Uncertain significance
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/variation/1716702/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-119148927-A-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-119278217-A-C?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005188.3%3Ac.1147…
- OncoKB ↗www.oncokb.org/gene/CBL/I383L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CBL+c.1147A%3EC
- 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= 6.20321e-07; MAF= 0.00006%, 1/1612068 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66644e-05; MAF= 0.00167%, 1/60008 alleles, homozygotes = 0).
gnomAD v2.1
This 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).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1716702)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.786. BayesDel score = 0.134053.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.