Classification rationale

PM2PP3 VUS

SF3B1 c.2263C>T

NM_012433.3:c.2263C>T (p.Pro755Ser) in SF3B1 is a missense variant absent from population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.¹ In silico predictors support a deleterious effect: REVEL score 0.562 and SpliceAI max delta 0.44 (acceptor gain) meet PP3 at supporting strength.² No pathogenic or benign classifications are available in ClinVar. No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified.³ With two supporting pathogenic criteria (PM2 and PP3) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.⁴

PM2 + PP3 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelspliceai ↗

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

Gene diagram · NM_012433.3 · variants mapped to exon structure

SF3B1 NM_012433.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with an allele frequency well below the 0.1% PM2 threshold.

Absent from gnomAD v2.1 exomes.Absent from gnomAD v4.1 exomes.Absent from gnomAD-Canada v1.0 genomes.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

Multiple lines of in silico evidence support a deleterious effect. REVEL score of 0.562 exceeds the 0.5 threshold for deleterious prediction. SpliceAI predicts a possible splice impact with a max delta score of 0.44 (acceptor gain, DS_AG=0.44).

REVEL score 0.562 (deleterious prediction).SpliceAI max delta 0.44 (acceptor gain DS_AG=0.44).BayesDel score 0.112595 (below deleterious threshold

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No prior report of this exact nucleotide change as pathogenic in ClinVar or the literature.

PS2 No de novo observation with confirmed maternity and paternity is available for this variant.

PS3 No variant-specific well-established functional studies were identified.

PS4 No case-control studies comparing variant prevalence in affected individuals versus controls are available.

PM1 This variant does not lie within a statistically significant mutational hotspot per Cancer Hotspots analysis, and no gene-specific functional domain PM1 rule is available.

PM5 No pathogenic missense variant has been identified at residue Pro755 to serve as a same-residue comparator.

PM6 No de novo observation (with or without confirmed parentage) is available for this variant.

PP1 No co-segregation data are available for this variant.

PP2 HCI prior probability score is not available for SF3B1.

PP4 No patient phenotype information is available for assessment of phenotypic specificity.

PP5 This variant has not been reported as pathogenic by a reputable source.

Benign

BA1 The variant is absent from gnomAD; the allele frequency does not exceed the 1% BA1 threshold.

BS1 The variant is absent from gnomAD; the allele frequency does not exceed the 0.3% BS1 threshold.

BS2 No observations of this variant in healthy adults are available to assess BS2.

BS3 No well-established functional studies demonstrating no damaging effect of this variant are available.

BS4 No non-segregation data are available for this variant.

BP1 SF3B1 missense variants are a known disease mechanism.

BP2 No observation of this variant in trans with a known dominant pathogenic variant is available.

BP4 In silico predictors do not support a benign interpretation.

BP5 No alternate molecular basis for the observed phenotype has been identified in a case with this variant.

BP6 This variant has not been reported as benign by a reputable source.

N/A · 2 PVS1 · 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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.44). REVEL score = 0.562. BayesDel score = 0.112595.

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. SF3B1, a component of the spliceosome complex, is frequently mutated in hematologic malignancies.

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; COSV59230199, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?