About RAF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAF1 c.1193G>T, p.(Arg398Leu)
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 ClinGen RAF1 VCEP v2.3.0. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RAF1 PM2 requirement for absence from controls.
PP3Supporting
PP3 · supporting
For this missense variant, REVEL is 0.861, which is above the RAF1 PP3 threshold of 0.7. BayesDel is 0.342905, which is directionally consistent with a damaging missense effect, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. Overall, the computational evidence supports a deleterious missense effect rather than an abnormal splicing mechanism.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. RAF1 (CRAF), an intracellular kinase and component of the pro-oncogenic MAP-kinase signaling pathway, is infrequently mutated in cancer. Germline muta
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen RAF1 VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The RAF1 c.1193G>T (p.Arg398Leu) variant has been reported in ClinVar, where the ClinGen RASopathy Variant Curation Expert Panel classified it as uncertain significance and additional clinical laboratories have submitted both likely pathogenic and uncertain significance assertions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with PM2_Supporting under the RAF1 RASopathy specification.
For this missense change, REVEL is 0.861, which exceeds the RAF1 PP3 threshold of 0.7; BayesDel is 0.342905; and SpliceAI predicts no significant splice effect with a maximum delta score of 0.10.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RAF1 PM2 requirement for absence from controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
PP3 SupportingFor this missense variant, REVEL is 0.861, which is above the RAF1 PP3 threshold of 0.7. BayesDel is 0.342905, which is directionally consistent with a damaging missense effect, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. Overall, the computational evidence supports a deleterious missense effect rather than an abnormal splicing mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.861
- BayesDel 0.342905
- SpliceAI max delta 0.10
Sources
Not met · 4 · evaluated, threshold not reached
PM1 The RAF1 specification limits PM1 to the CR2 domain (amino acids 251-266/exon 7), exon 14, or exon 17. This variant is p.Arg398Leu in exon 11, so it is outside the specified RAF1 PM1 regions and PM1 is not met. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain [AA 251-266/exon7], exon 14, exon 17). Not applicable to specific amino acid residues (see PM5).
Evidence considered
- Variant: p.Arg398Leu
- Transcript position c.1193G>T
- RAF1 VCEP PM1 domains restricted to CR2/exon 7
- exon 14
- and exon 17
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RAF1 BA1 threshold of 0.05%, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- RAF1 VCEP BA1 threshold: filtering allele frequency >=0.05%
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the RAF1 BS1 threshold of 0.025%, so BS1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- RAF1 VCEP BS1 threshold: filtering allele frequency >=0.025%
Sources
BP4 For this missense variant, REVEL is 0.861, which is above the RAF1 BP4 benign threshold of 0.3, so BP4 is not met. BayesDel is 0.342905, and SpliceAI shows no significant splice impact with a maximum delta score of 0.10, but the missense prediction does not support a benign computational interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.861
- BayesDel 0.342905
- SpliceAI max delta 0.10
Sources
Not assessed · 11 · no assessment recorded
PS1 PS1 requires the same amino acid change as a previously established pathogenic variant. No such same-amino-acid pathogenic comparison was identified in the available ClinVar summary or RAF alignment materials, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in BRAF and RAF1.
Evidence considered
- ClinVar summary available for p.Arg398Leu
- RAF alignment materials reviewed
Still missing
- Direct evidence for a previously established pathogenic variant producing the same RAF1 p.Arg398Leu amino acid change was not identified.
Sources
PS2 No confirmed de novo occurrence with sufficient parental testing detail was identified in the available evidence, so PS2 was not assessed. Details ▾Hide ▴
Rule
Very Strong: 4 Points. Strong: 2 Points. Moderate: 1 Point.
Evidence considered
- ClinVar summary reviewed for case-level assertions
Still missing
- Published or submitted case-level evidence confirming de novo occurrence was not identified.
- Parental relationship confirmation and phenotype detail were not available.
Sources
PS3 The RASopathy VCEP functional-study materials identify approved assay types for RAF1, but no variant-specific approved functional result for p.Arg398Leu was identified in the available evidence. PS3 was therefore not assessed. Details ▾Hide ▴
Rule
Moderate: Two or more different approved assays. Supporting: One approved assay.
Evidence considered
- Approved RAF1 kinase and pathway assay framework reviewed
- No reviewed variant-specific functional evidence identified in curated cancer database
Still missing
- Variant-specific results from one or more approved RAF1/RASopathy functional assays were not identified.
Sources
PS4 This variant meets PM2_Supporting because it is absent from gnomAD, but the available evidence does not provide enough unrelated affected observations to assign the RAF1 PS4 point-based threshold. PS4 was not assessed. Details ▾Hide ▴
Rule
Strong: ≥5 points. Moderate: ≥3 points. Supporting: ≥1 points.
Evidence considered
- ClinVar: expert panel VUS and additional laboratory submissions
- gnomAD absence supports prerequisite rarity
Still missing
- Case-level counts for unrelated affected individuals with this exact variant were not identified.
- The RAF1 PS4 points threshold could not be calculated from the available evidence.
Sources
PM5 PM5 requires a different established pathogenic or likely pathogenic missense change at the same codon. No qualifying codon 398 comparison was identified in the available RAF alignment materials, so PM5 was not assessed. Details ▾Hide ▴
Rule
Strong: ≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands. Moderate: 1 [likely] pathogenic residue change at the same codon.
Evidence considered
- RAF alignment materials reviewed for codon-level comparisons
Still missing
- A validated same-codon RAF1 codon 398 pathogenic comparison was not identified in the available materials.
Sources
vcep_raf_alignmentcspec ↗
PM6 No assumed de novo or incompletely confirmed de novo occurrence was identified in the available evidence, so PM6 was not assessed. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in unaffected individuals of an appropriate age and phenotype context, so BS2 was not assessed. Details ▾Hide ▴
BS4 No non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
BP2 No evidence was identified for this variant occurring with an alternative molecular explanation for a RASopathy in the same case, so BP2 was not assessed. Details ▾Hide ▴
BP5 No evidence was identified for a separate molecular explanation fully accounting for the phenotype, so BP5 was not assessed. Details ▾Hide ▴
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, not a nonsense, frameshift, or canonical splice variant, and the RAF1 specification marks PVS1 as not applicable. Details ▾Hide ▴
Evidence considered
- Variant type: missense
- PVS1 scaffold: not a default null-variant bucket
Sources
PM3 N/AThe RAF1 specification marks PM3 as not applicable. Details ▾Hide ▴
PM4 N/APM4 addresses protein length changes such as in-frame insertions, deletions, or stop-loss variants. This variant is a missense substitution without a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
No known repetitive areas in gene. Use as described.
Evidence considered
- Variant type: missense
Sources
PP2 N/AThe RAF1 specification marks PP2 as not applicable. Details ▾Hide ▴
PP4 N/AThe RAF1 specification marks PP4 as not applicable. Details ▾Hide ▴
PP5 N/AThe RAF1 specification marks PP5 as not applicable. Details ▾Hide ▴
BS3 N/AThe RAF1 specification marks BS3 as not applicable. Details ▾Hide ▴
BP1 N/AThe RAF1 specification uses BP1 for truncating variants in the relevant gene context. This variant is a missense change, so BP1 is not applicable. Details ▾Hide ▴
Rule
This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant ... in genes without established LOF correlation to disease.
Evidence considered
- Variant type: missense
Sources
BP3 N/AThe RAF1 specification marks BP3 as not applicable. Details ▾Hide ▴
BP6 N/AThe RAF1 specification marks BP6 as not applicable. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain intronic/non-coding variants with no predicted splice impact. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous (silent) variant ... This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants ...
Evidence considered
- Variant type: missense
- SpliceAI max delta 0.10
Sources
Identifiers
- Gene
- RAF1
- Transcript
- NM_002880.4
- Coding (HGVS c.)
- NM_002880.4:c.1193G>T
- Protein (HGVS p.)
- NP_002871.1:p.(Arg398Leu)
- GRCh38
- chr3:12591708 C>A
- GRCh37
- chr3:12633207 C>A
Gene diagram
Every interpreted variant in RAF1, mapped onto the exon structure of NM_002880.4. Select a row to find it on the plot.
RAF1NM_002880.4
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 RAF1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingFor this missense variant, REVEL is 0.861, which is above the RAF1 PP3 threshold of 0.7. BayesDel is 0.342905, which is directionally consistent with a damaging missense effect, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.10. Overall, the computational evidence supports a deleterious missense effect rather than an abnormal splicing mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.861
- BayesDel 0.342905
- SpliceAI max delta 0.10
Sources
BP4 For this missense variant, REVEL is 0.861, which is above the RAF1 BP4 benign threshold of 0.3, so BP4 is not met. BayesDel is 0.342905, and SpliceAI shows no significant splice impact with a maximum delta score of 0.10, but the missense prediction does not support a benign computational interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.861
- BayesDel 0.342905
- SpliceAI max delta 0.10
Sources
BP7 N/ABP7 applies to synonymous or certain intronic/non-coding variants with no predicted splice impact. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous (silent) variant ... This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants ...
Evidence considered
- Variant type: missense
- SpliceAI max delta 0.10
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.861. BayesDel score = 0.342905.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243110
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/40614/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-12633207-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-12591708-C-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002880.4%3Ac.1193…
- OncoKB ↗www.oncokb.org/gene/RAF1/R398L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105217175
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.861. BayesDel score = 0.342905.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAF1 (CRAF), an intracellular kinase and component of the pro-oncogenic MAP-kinase signaling pathway, is infrequently mutated in cancer. Germline muta
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52583001, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.