Variant classification summary

NM_001654.5:c.641C>G

ARAF · NP_001645.1:p.(Ser214Cys) · NM_001654.5

GRCh37: chrX:47426121 C>G · GRCh38: chrX:47566722 C>G

Gene: ARAF Transcript: NM_001654.5

Final call

VUS

PM1 moderate PM2 supporting

Variant details

Gene

ARAF

Transcript

NM_001654.5

Protein

NP_001645.1:p.(Ser214Cys)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 Moderate: ARAF S214 is a reported statistically significant mutational hotspot and the exact variant is absent from gnomAD.

2

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Moderate pathogenic criterion plus one Supporting pathogenic criterion is insufficient for a classified pathogenic call, and no benign combination is met; therefore the result is VUS.

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
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no previously established pathogenic variant with the same Ser214Cys amino-acid change was identified, and ClinVar has no exact record.	clinvar PMID:24569458
PS2	Not assessed	Not assessed: no proband phenotype, family-history information, or confirmed maternity and paternity results are available to establish a de novo variant.
PS3	Not assessed	Not assessed: ARAF S214C transformed airway epithelial cells, but assay controls, quantitative results, and reproducibility are insufficiently documented for well-established PS3 evidence.	PMID:24569458
PS4	Not assessed	Not assessed: the only variant-specific paper reports one affected patient but no exact-variant control count, so the required OR >5.0 and 95% CI excluding 1.0 cannot be calculated.	PMID:24569458
PM1	Met	Met at moderate strength: ARAF S214 is reported as a statistically significant hotspot, while the variant is absent from gnomAD v2.1 and v4.1.	hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive inheritance evidence, pathogenic allele, affected-proband observation, or parental testing establishes a pathogenic variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense substitution at ARAF residue 214 was established as pathogenic; the available report concerns the same S214C change.	clinvar PMID:24569458 pm5_candidates
PM6	Not assessed	Not assessed: no proband phenotype or documented assumed de novo occurrence without confirmed maternity and paternity is available.
PP1	Not assessed	Not assessed: no affected relatives or family variant-status results are available to evaluate co-segregation or meioses.
PP2	Not assessed	Not assessed: gene-wide evidence for low benign missense variation and a common disease-causing missense mechanism is unavailable.
PP3	Not met	Not met: the applicable REVEL-only missense path has no score available, so no calibrated PP3 threshold can be met.	bayesdel spliceai
PP4	Not assessed	Not assessed: no sufficiently specific patient phenotype or family history for a single-gene disease is supplied for applying PP4.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification to satisfy the PP5 requirement.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no frequency approaching the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the generic BS1 frequency threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier, homozygote, or hemizygote observation is reported for this variant.
BS3	Not assessed	Not assessed: the available study reports sorafenib-sensitive cellular transformation, not a well-established absence of damaging effect on ARAF function or splicing.	PMID:24569458
BS4	Not assessed	Not assessed: no affected relatives, reliable phenotypes, or relative genotypes are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: evidence that ARAF disease is caused primarily by truncating variants is unavailable.
BP2	Not assessed	Not assessed: no fully penetrant dominant context or pathogenic allele with documented trans or cis phase is available for this variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the applicable REVEL-only missense path has no score available, so no calibrated BP4 threshold can be met.	bayesdel spliceai
BP5	Not assessed	Not assessed: no case is documented with an alternate molecular basis that could satisfy BP5.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification to satisfy the BP6 requirement.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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