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LYFE SCIENCES
Project: HERA
NM_002880.4:c.1193G>T
p.Arg398Leu  ·  RAF1
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Classification rationale
1

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.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with PM2_Supporting under the RAF1 RASopathy specification.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

spliceai ↗ cspec ↗
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
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Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
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).
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. RAF1 (CRAF), an intracellular kinase and component of the pro-oncogenic MAP-kinase signaling pathway, is infrequently mutated in cancer. Germline muta
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.861. BayesDel score = 0.342905.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52583001, n = 4 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR398
Hotspots ↗