SF3B1

Chr 2

splicing factor 3b subunit 1

Also known as: Hsh155, MDS, PRP10, PRPF10, SAP155, SF3b155

NCBI Gene: 23451 ENSG00000115524 UniProt: O75533 OMIM: 605590

This gene encodes subunit 1 of the splicing factor 3b protein complex, which is essential for pre-mRNA splicing by recognizing branch sites and anchoring U2 snRNP to pre-mRNA during spliceosome assembly. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.066), suggesting that heterozygous mutations would likely cause severe developmental disorders, though specific Mendelian phenotypes have not yet been established in OMIM. Currently, SF3B1 mutations are only documented in somatic myelodysplastic syndrome, but the high constraint scores indicate this gene may be associated with uncharacterized neurodevelopmental conditions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.071 OMIM phenotype

Clinical Summary— SF3B1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 47 VUS of 98 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 7.76

OE 0.01 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

7.70Z-score

OE missense 0.19 (0.17–0.22)

141 obs / 723.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.07)

0≤0.351.4

Missense OE?0.19 (0.17–0.22)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 72.1Missense obs/exp: 141 / 723.9Syn Z: 0.28

This gene — mechanism propensity

0.3197th %ile

GOF

0.3590th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.07

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

98 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic4

VUS47

Likely Benign9

Benign12

Conflicting1

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	4	0	0	4
VUS	6	41	0	0	47
Likely Benign	0	0	3	6	9
Benign	0	0	2	10	12
Conflicting	—				1
Total	6	45	5	16	73

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

36 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap SF3B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SF3B1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Myelodysplastic Syndromes

Monitoring Mutational Burden in Low Risk MDS Patients Using Sequential Peripheral Blood Samples

RECRUITING

NCT04251078Josep Carreras Leukaemia Research InstituteStarted 2019-01-01

Myeloproliferative Neoplasm

Impact of Epigenetic Age on Clinic-biological Presentation and Prognosis in Myeloproliferative Neoplasms Epigenetic Age in Myeloproliferative Neoplasms (EpiC)

RECRUITING

NCT06022328University Hospital, BordeauxStarted 2023-12-15

Assessment of the epigenetic age

Myelodysplastic SyndromesMyeloproliferative NeoplasmAnemia

Luspatercept for Anemia in Lower Risk MDS or Non-proliferative MDS/MPN Neoplasms

ACTIVE NOT RECRUITING

NCT05732961Phase PHASE2H. Lee Moffitt Cancer Center and Research InstituteStarted 2023-02-21

Luspatercept

Metastatic Solid TumorSF3B1 Gene MutationSpliceosome Mutation

Patient Response to Immunotherapy Using Spliceosome Mutational Markers (PRISMM)

ACTIVE NOT RECRUITING

NCT04447651Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsStarted 2020-09-17