GeneBe

SF3B4

protein-coding

splicing factor 3b subunit 4, the group of SF3b complex|RNA binding motif containing

Gene summary

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]

MANE transcript

NM_005850.5

Inheritance

AD

ClinVar variants

P:51U:55B:42

Top phenotype

Acrofacial dysostosis 1, Nager type

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:149,923,317-149,927,803

External References & Databases

Ensembl (ENSG00000143368)NCBI Gene (10262)OMIM (605593)HGNC:10771GenCCUniProt (Q15427)AlphaFoldClinVar (SF3B4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~4.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Nager acrofacial dysostosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007943

Submitter: Orphanet

Nager acrofacial dysostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007943

Submitter: G2P

SF3B4-related acrofacial dysostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800483

Submitter: ClinGen

*SF3B4* was first reported in relation to autosomal dominant SF3B4-related acrofacial dysostosis in 2012 (Bernier et al., PMID: 22541558). SF3B4 has been noted to be associated with the following disease entities: Nager acrofacial dysostosis and Rodriguez acrofacial dysostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, SF3B4-related acrofacial dysostosis (MONDO:0800483). Six variants (1 start-loss, 4 frameshift, 1 nonsense) that have been reported in 11 probands in 2 publications (PMID: 22541558, PMID: 23568615) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be LOF. This gene-disease association is also supported by experimental evidence (animal models and expression level evidence) (PMID: 26874011, 31900962, 9097020). SF3B4 KD Xenopus models and heterozygous SF3B4 mutant mice models demonstrated some features of Nager syndrome (PMID: 26874011, 31900962). Additionally, the gene has been shown to be expressed in areas of interest in mice (PMID: 9097020). In summary, *SF3B4* is definitively associated with autosomal dominant SF3B4-related acrofacial dysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 05/18/2023. (Gene Clinical Validity Standard Operating Procedures Version 9).

Nager acrofacial dysostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007943

Submitter: PanelApp Australia

Nager acrofacial dysostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007943

Submitter: Ambry Genetics

Nager acrofacial dysostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007943

Submitter: Labcorp Genetics (formerly Invitae)

acrofacial dysostosis Rodriguez typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008714

Submitter: Orphanet

Clinical Genomic Database (CGD)

Acrofacial dysostosis 1, Nager typeAD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22541558; 23568615Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SF3B4 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 71
Nager syndromeTotal: 41
Inborn genetic diseasesTotal: 35
not specifiedTotal: 27
SF3B4-related disorderTotal: 23
Genetic hearing lossTotal: 1
Cleft palateTotal: 1
Metaphyseal chondrodysplasia, Schmid typeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005850.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
5
clinvar
33
clinvar
2
clinvar
 41
missense
45
clinvar
7
clinvar
 52
nonsense
8
clinvar
1
clinvar
2
clinvar
 11
start loss
3
clinvar
 3
frameshift
27
clinvar
7
clinvar
1
clinvar
 35
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
2
clinvar
 6
Total411055402148

Highest pathogenic variant AF is 0.000014550216

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005850.5RefSeqNP_005841.16MANE Select
ENST00000271628.9EnsemblENSP00000271628.86MANE Select
ENST00000457312.1EnsemblENSP00000391114.12Standard
ENST00000940764.1EnsemblENSP00000610823.16Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
sf3b4Danio rerio

Structure: trunk

Quality: necrotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Spliceosome - Homo sapiens (human)
  • mRNA Processing
  • Metabolism of RNA
  • mRNA Splicing - Major Pathway
  • mRNA Splicing - Minor Pathway

Biological Process

  • RNA splicing, via transesterification reactions
  • mRNA splicing, via spliceosome
  • mRNA processing
  • RNA splicing
  • positive regulation of mRNA splicing, via spliceosome

Molecular Function

  • RNA binding
  • protein binding

Cellular Component

  • nucleus
  • nucleoplasm
  • spliceosomal complex
  • U12-type spliceosomal complex
  • nucleolus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000271628
Coding exons
6
Length
5028
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.87702380.2940.00001262708
Missense (PolyPhen)255.3070.036161651
Synonymous-0.6519789.21.090.00000466944
Loss of Function3.51014.40.009.36e-7161

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex. SF3B4 has been found in complex 'B' and 'C' as well (PubMed:10882114). Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron (PubMed:15146077). {ECO:0000269|PubMed:10882114, ECO:0000269|PubMed:12234937, ECO:0000269|PubMed:15146077, ECO:0000269|PubMed:27720643}.;
Disease
DISEASE: Acrofacial dysostosis 1, Nager type (AFD1) [MIM:154400]: A form of acrofacial dysostosis, a group of disorders which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of AFD1 include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hyoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. {ECO:0000269|PubMed:22541558}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.113

Intolerance Scores

RVIS EVS
-0.3
RVIS percentile EVS
32.62

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.995

Gene Damage Prediction

AllRecessiveDominant
MendelianLowLowLow
Primary ImmunodeficiencyMediumLowMedium
CancerLowLowLow
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