Human Gene Module / Chromosome 11 / SF1

SF1splicing factor 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
11q13.1
Associated Disorders
-
Relevance to Autism

Bou-Rouphael et al., 2025 described a cohort of 15 unrelated individuals with de novo likely deleterious variants in the SF1 gene presenting with neurodevelopmental disorders of variable severity; all individuals presented with developmental delay during the first years of life and mild facial features, and autism spectrum disorder was the most common neurodevelopmental disorder among individuals aged 3 years of older (n=9). Additional functional studies in neuronal progenitor cells in this report demonstrated that SF1 downregulation altered gene expression and alternative splicing programs, particularly in genes involved in neuronal differentiation, synaptic transmission, and axonal guidance. Ultra-rare de novo non-coding variants in the SF1 gene have been previously reported in ASD probands from the Simons Simplex Collection (Iossifov et al, 2014).

Molecular Function

This gene encodes a nuclear pre-mRNA splicing factor. The encoded protein specifically recognizes the intron branch point sequence at the 3' splice site, together with the large subunit of U2 auxiliary factor (U2AF), and is required for the early stages of spliceosome assembly. It also plays a role in nuclear pre-mRNA retention and transcriptional repression. The encoded protein contains an N-terminal U2AF ligand motif, a central hnRNP K homology motif and quaking 2 region which bind a key branch-site adenosine within the branch point sequence, a zinc knuckles domain, and a C-terminal proline-rich domain.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to SF1 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary - Johnny Bou-Rouphael et al. (2025) Yes ADHD, ID, epilepsy/seizures
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*380A>G - 3_prime_UTR_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1403-6C>G p.? splice_region_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.31+17del p.? intron_variant Unknown - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.278G>A p.Arg93Gln missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.362C>T p.Pro121Leu missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.532C>T p.Arg178Trp missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.611A>G p.His204Arg missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.844T>C p.Cys282Arg missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.959T>C p.Leu320Pro missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.1262C>A p.Pro421Gln missense_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.64dup p.Trp22LeufsTer43 frameshift_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.1639C>T p.Gln547Ter stop_gained Unknown Not maternal Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.221del p.Pro74LeufsTer63 frameshift_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.298del p.Arg100AlafsTer37 frameshift_variant Unknown - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.552del p.Glu185LysfsTer38 frameshift_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.1764_1767delinsT p.Pro590del inframe_deletion De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
c.1523dup p.Pro509AlafsTer103 frameshift_variant De novo - Simplex 40987292 Johnny Bou-Rouphael et al. (2025)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2025
1

Initial score established: 1

Krishnan Probability Score

Score 0.49278656898127

Ranking 4401/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99885501695135

Ranking 1098/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Zhang D Score

Score 0.33257225688335

Ranking 2254/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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