Variant classification summary

NM_002880.4:c.1193G>T

RAF1 · NP_002871.1:p.(Arg398Leu) · NM_002880.4

GRCh37: chr3:12633207 C>A · GRCh38: chr3:12591708 C>A

Gene: RAF1 Transcript: NM_002880.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

RAF1

Transcript

NM_002880.4

Protein

NP_002871.1:p.(Arg398Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

2

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

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RAF1 PM2 requirement for absence from controls.	gnomad_v2 gnomad_v4 cspec
PP3	Met	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 bayesdel spliceai cspec
BP4	Not met	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.	revel bayesdel spliceai cspec
PM1	Not met	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.	cspec
PVS1	N/A	This variant is a missense substitution, not a nonsense, frameshift, or canonical splice variant, and the RAF1 specification marks PVS1 as not applicable.	cspec pvs1_gene_context pvs1_variant_assessment
BP1	N/A	The RAF1 specification uses BP1 for truncating variants in the relevant gene context. This variant is a missense change, so BP1 is not applicable.	cspec
BP7	N/A	BP7 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.	cspec spliceai
PM4	N/A	PM4 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.	cspec
BP3	N/A	The RAF1 specification marks BP3 as not applicable.	cspec
PM3	N/A	The RAF1 specification marks PM3 as not applicable.	cspec
BP6	N/A	The RAF1 specification marks BP6 as not applicable.	cspec
PP5	N/A	The RAF1 specification marks PP5 as not applicable.	cspec
PP4	N/A	The RAF1 specification marks PP4 as not applicable.	cspec
PP2	N/A	The RAF1 specification marks PP2 as not applicable.	cspec
BS3	N/A	The RAF1 specification marks BS3 as not applicable.	cspec
PS1	Not assessed	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.	clinvar vcep_raf_alignment cspec
PM5	Not assessed	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.	vcep_raf_alignment cspec
PS3	Not assessed	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.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb cspec
PS4	Not assessed	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.	clinvar gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	No confirmed de novo occurrence with sufficient parental testing detail was identified in the available evidence, so PS2 was not assessed.	clinvar cspec
PM6	Not assessed	No assumed de novo or incompletely confirmed de novo occurrence was identified in the available evidence, so PM6 was not assessed.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	clinvar cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals of an appropriate age and phenotype context, so BS2 was not assessed.	clinvar cspec
BP2	Not assessed	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.	clinvar cspec
BP5	Not assessed	No evidence was identified for a separate molecular explanation fully accounting for the phenotype, so BP5 was not assessed.	clinvar cspec

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