Analysis in progress

Initialising…

complete

This report is still being assembled — sections appear as each stage finishes. It isn't final yet.

SF3B1

Final classification

VUS

SF3B1 c.2263C>T · p.Pro755Ser

SF3B1

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.

Gene

SF3B1

Transcript

NM_012433.3

HGVS · transcript:coding

NM_012433.3:c.2263C>T

Consequence

N/A

GRCh38

chr2:197401849 G>A

GRCh37

chr2:198266573 G>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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