NM_012433.3:c.2352G>A

SF3B1 · NP_036565.2:p.(Met784Ile) · NM_012433.3

GRCh37: chr2:198266484 C>T · GRCh38: chr2:197401760 C>T

Gene: SF3B1 Transcript: NM_012433.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

SF3B1

Transcript

NM_012433.3

Protein

NP_036565.2:p.(Met784Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_012433.3:c.2352G>A (p.Met784Ile) is a missense variant in SF3B1, a gene encoding a core spliceosome component associated with both somatic malignancy and constitutional neurodevelopmental disorders.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0.0), meeting PM2 at moderate strength.

Multiple in silico predictors suggest no significant impact: BayesDel score is 0.179 (benign range) and SpliceAI predicts no splicing alteration (max delta = 0.02), meeting BP4 at supporting benign strength. REVEL score of 0.538 is intermediate.

The variant is absent from ClinVar and has not been reported in the published literature as a germline variant. COSMIC records one somatic occurrence (COSV106472208) without functional characterization.

No variant-specific functional studies (PS3), de novo observations (PS2/PM6), co-segregation data (PP1), or case-control data (PS4) are available. Computational evidence is equivocal (PP3 not met). No pathogenic comparator at the same residue exists (PM5 not met).

The variant does not lie in a statistically significant hotspot (cancerhotspots.org) and position 784 is not a recognized recurrent mutation site (PM1 not met). SF3B1 germline disease involves both missense and loss-of-function variants (PMID:41577671), so BP1 does not apply.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient for classification. The variant remains a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense variant (p.Met784Ile); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The generic PVS1 framework assessment confirms variant_bucket='other' and does not trigger PVS1.	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at codon 784 producing the same amino acid change (p.Met784Ile) has been established as pathogenic. PS1 requires a different nucleotide substitution resulting in the identical amino acid change with an established pathogenic classification.
PS2	Not assessed	No de novo testing data with confirmed paternity and maternity is available for this variant.
PS3	Not met	No variant-specific functional studies have been performed for NM_012433.3:c.2352G>A (p.Met784Ile). OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. The single COSMIC somatic report (COSV106472208) lacks functional characterization and does not meet PS3 requirements.	oncokb
PS4	Not assessed	No case-control or cohort prevalence data are available to assess enrichment of this variant in affected individuals compared to controls.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion.
PM1	Not met	The variant (p.Met784Ile) does not lie within a statistically significant mutational hotspot per cancerhotspots.org, and position 784 is not a recognized recurrent somatic mutation site in SF3B1. While SF3B1 HEAT domain mutations are common in cancer, the known hotspots cluster at residues K700, R625, K666, H662, and E902 — not at M784. Without residue-specific hotspot or critical functional domain evidence for position 784, PM1 is not met.	oncokb
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (allele frequency = 0.0). Under generic ACMG/AMP 2015, absence from large population cohorts meets PM2 at moderate strength for a dominant disorder with AF well below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Met784) has been identified. PM5 requires a different missense change at the same codon with an established pathogenic classification. The automated PM5 candidate search returned zero same-residue candidates.	pm5_candidates
PM6	Not assessed	No de novo observation data are available for this variant. PM6 requires reported de novo occurrence without confirmed paternity and maternity.
PP1	Not assessed	No family co-segregation data are available for this variant.
PP2	Not assessed	HCI prior constraint data are not available for SF3B1; the gene is not in the HCI prior database. Without a gene-level missense constraint metric (z-score or HCI prior), the low rate of benign missense variation cannot be determined for PP2.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.538 (intermediate, below the typical pathogenic threshold of >0.75). BayesDel score is 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing impact (max delta = 0.02). The in silico evidence is equivocal and does not meet PP3 requirements for multiple concordant damaging predictions.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available to assess whether the presentation is highly specific for SF3B1-related disease.
PP5	N/A	PP5 is not a standard ACMG/AMP 2015 criterion.
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). BS1 requires an allele frequency >0.3% under non-VCEP generic ACMG rules.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in any healthy individuals in population databases. BS2 requires observation in a healthy adult homozygous state (for a dominant disorder) or in trans with a pathogenic variant (for a recessive disorder).	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not assessed	No family segregation data demonstrating non-segregation with disease are available.
BP1	Not met	SF3B1 germline disease is associated with both missense and loss-of-function variants. A recent cohort study (PMID:41577671) reports 17 individuals with constitutional missense variants and 9 with predicted loss-of-function variants, both associated with neurodevelopmental disorders. Missense variants are a well-established disease mechanism in SF3B1, so BP1 does not apply.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic dominant variant are available.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign score of 0.179 (below the damaging threshold of ~0.27). SpliceAI predicts no splicing alteration (max delta score = 0.02). REVEL score of 0.538 is intermediate and does not overturn the two concordant benign/neutral predictions.	revel bayesdel spliceai
BP5	Not assessed	No data are available to determine whether an alternative molecular basis for disease has been identified in a case carrying this variant.
BP6	Not met	The variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	NM_012433.3:c.2352G>A is a missense variant (p.Met784Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a substitution variant.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; SF3B1-associated disorders follow autosomal dominant inheritance.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame indels, stop-loss); this is a missense substitution.

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