SF3B4

Chr 1AD

splicing factor 3b subunit 4

Also known as: AFD1, Hsh49, SAP49, SF3b49

NCBI Gene: 10262 ENSG00000143368 UniProt: Q15427 OMIM: 605593

The protein is a component of the SF3B subcomplex within the U2 snRNP spliceosome that recognizes branch sites and promotes pre-mRNA splicing. Mutations cause acrofacial dysostosis 1 (Nager type), which primarily affects craniofacial and limb development, following an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants, indicating that heterozygous mutations are likely sufficient to cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.211 OMIM phenotype

Clinical Summary— SF3B4

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Gene-Disease Validity (ClinGen)

SF3B4-related acrofacial dysostosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

47 unique Pathogenic / Likely Pathogenic· 47 VUS of 160 total submissions

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?

0.21LOEUF

pLI 0.992

Z-score 3.51

OE 0.00 (0.00–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.87Z-score

OE missense 0.29 (0.24–0.36)

70 obs / 237.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.21)

0≤0.351.4

Missense OE?0.29 (0.24–0.36)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 0 / 14.4Missense obs/exp: 70 / 237.8Syn Z: -0.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSF3B4-related acrofacial dysostosis, Nager typeLOFAD

This gene — mechanism propensity

0.3991th %ile

GOF

0.3590th %ile

LOF

0.81top 5%

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

LOFprediction above median · 1 literature citation · 91% of P/LP variants are LoF · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFNager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause.1

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

References

1.PMID 24003905 ↗

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41

Likely Pathogenic6

VUS47

Likely Benign37

Benign16

Conflicting4

Pathogenic

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	37	3	0	1	41
Likely Pathogenic	6	0	0	0	6
VUS	2	40	2	3	47
Likely Benign	0	5	4	28	37
Benign	0	0	12	4	16
Conflicting	—				4
Total	45	48	18	36	151

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap SF3B4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →