Classification rationale

PM2PP3 VUS

RAF1 c.1193G>T

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.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with PM2_Supporting under the RAF1 RASopathy specification.² 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 0.10.³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelbayesdelspliceai ↗cspec ↗

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.

Gene diagram · NM_002880.4 · variants mapped to exon structure

RAF1 NM_002880.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RAF1 PM2 requirement for absence from controls.

gnomAD v2.1: absentgnomAD v4.1: absent

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 supporting Pathogenic

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.

REVEL 0.861BayesDel 0.342905SpliceAI max delta 0.10

spliceai ↗cspec ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS1 PS1 requires the same amino acid change as a previously established pathogenic variant.

PS2 No confirmed de novo occurrence with sufficient parental testing detail was identified in the available evidence, so PS2 was not assessed.

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.

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.

PM1 The RAF1 specification limits PM1 to the CR2 domain (amino acids 251-266/exon 7), exon 14, or exon 17.

PM5 PM5 requires a different established pathogenic or likely pathogenic missense change at the same codon.

PM6 No assumed de novo or incompletely confirmed de novo occurrence was identified in the available evidence, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

Benign

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.

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.

BS2 No evidence was identified showing this variant in unaffected individuals of an appropriate age and phenotype context, so BS2 was not assessed.

BS4 No non-segregation data were identified for this variant, so BS4 was not assessed.

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.

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.

BP5 No evidence was identified for a separate molecular explanation fully accounting for the phenotype, so BP5 was not assessed.

N/A · 11 PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

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 ↗

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 ↗

Functional 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 ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

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).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance