Human Gene Module / Chromosome 17 / SRSF1

SRSF1serine and arginine rich splicing factor 1

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
18 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
17q22
Associated Disorders
-
Relevance to Autism

Rare and potentially damaging missense variants in the SRSF1 gene have been previously identified in two ASD probands (Satterstrom et al., 2020; Zhou et al., 2022). Bogaert et al., 2023 identified a cohort of 17 individuals with heterozygous germline SRSF1 variants who presented with a neurodevelopmental syndrome characterized by developmental delay and intellectual disability, hypotonia, and neurobehavioral problems (includiing autistic features and/or stereotypy in a subset of affected individuals) with variable skeletal and cardiac abnormalities; functional assessment in Drosophila demonstrated that all loss-of-function variants and 5 out of 7 missense variants in this gene were pathogenic and resulted in loss of SRSF1 splicing activity, which correlated with a detectable and specific DNA methylation signature in blood-derived DNA from affected individuals.

Molecular Function

This gene encodes a member of the arginine/serine-rich splicing factor protein family. The encoded protein can either activate or repress splicing, depending on its phosphorylation state and its interaction partners.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to SRSF1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Primary - Bogaert E et al. (2023) No Autistic features, stereotypy, ADHD, epilepsy/seiz
4 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 37071997 Bogaert E et al. (2023)
c.535A>G p.Lys179Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.82C>T p.Arg28Ter stop_gained De novo - Simplex 37071997 Bogaert E et al. (2023)
c.97G>T p.Glu33Ter stop_gained De novo - Simplex 37071997 Bogaert E et al. (2023)
c.231T>G p.Tyr77Ter stop_gained De novo - Simplex 37071997 Bogaert E et al. (2023)
c.58G>A p.Val20Met missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.71C>T p.Pro24Leu missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.119G>T p.Gly40Val missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.130G>A p.Asp44Asn missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.208G>A p.Ala70Thr missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.251T>G p.Leu84Arg missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.478G>A p.Val160Met missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.548A>G p.His183Arg missense_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.579dup p.Val194SerfsTer2 frameshift_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.601del p.Ser201ValfsTer87 frameshift_variant De novo - Simplex 37071997 Bogaert E et al. (2023)
c.478G>A p.Val160Met missense_variant De novo (germline mosaicism) - Multiplex 37071997 Bogaert E et al. (2023)
c.58G>A p.Val20Met missense_variant De novo - Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
c.377_378del p.Ser126TrpfsTer17 frameshift_variant Unknown Not maternal Simplex 37071997 Bogaert E et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2023
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.56084429855447

Ranking 1307/25841 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 0.99199402292592

Ranking 1710/18225 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
Sanders TADA Score

Score 0.91840491548152

Ranking 8816/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.28150968672394

Ranking 3011/20870 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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