Human Gene Module / Chromosome 21 / SCAF4

SCAF4SR-related CTD associated factor 4

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
60 / 0
Aliases
SCAF4, SFRS15,  SRA4
Associated Syndromes
-
Chromosome Band
21q22.11
Associated Disorders
ASD, EPS
Relevance to Autism

Fliedner et al., 2020 described eleven individuals with heterozygous SCAF4 variants that presented with a neurodevelopmental disorder characterized by developmental delay and intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies; five individuals in this cohort were reported to have autism, while an additional two individuals presented with autistic features.

Molecular Function

This gene likely encodes a member of the arginine/serine-rich splicing factor family. A similar protein in Rat appears to bind the large subunit of RNA polymerase II and provide a link between transcription and pre-mRNA splicing.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SCAF4 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
2 Primary Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing Fliedner A et al. (2020) No ASD or autistic features, epilepsy/seizures
3 Support - Wilfert AB et al. (2021) Yes -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Wang J et al. (2023) Yes -
7 Support - Axel Schmidt et al. (2024) No Epilepsy/seizures
8 Support - Cosima M Schmid et al. () No ASD or autistic features, ADHD, epilepsy/seizures,
Rare Variants   (60)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1023+3A>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.276+1G>T - splice_site_variant De novo - - 32730804 Fliedner A et al. (2020)
- p.Tyr40Cys missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1301C>A p.Ser434Ter stop_gained De novo - - 32730804 Fliedner A et al. (2020)
c.1889G>A p.Trp630Ter stop_gained De novo - - 32730804 Fliedner A et al. (2020)
c.526C>T p.Gln176Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.783G>T p.Leu261Phe missense_variant De novo - - 32730804 Fliedner A et al. (2020)
c.38C>T p.Ser13Leu missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1569+1G>C - splice_site_variant De novo - Simplex 32730804 Fliedner A et al. (2020)
c.1423C>T p.Arg475Ter stop_gained De novo - Simplex 32730804 Fliedner A et al. (2020)
c.571C>T p.Gln191Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.697C>T p.Gln233Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1532G>A p.Trp511Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.1045C>T p.Gln349Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1363C>T p.Arg455Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1450C>T p.Arg484Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1471C>T p.Arg491Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1696G>T p.Gly566Ter stop_gained De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.3152G>T p.Arg1051Ile missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1812G>A p.Trp604Ter stop_gained Familial Maternal - 32730804 Fliedner A et al. (2020)
c.32T>C p.Leu11Pro missense_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1514-2A>G p.? splice_site_variant Unknown - Unknown 39668183 Cosima M Schmid et al. ()
c.1339C>T p.Arg447Ter stop_gained De novo - Multiplex 39668183 Cosima M Schmid et al. ()
c.2041C>T p.Gln681Ter stop_gained De novo - Multiplex 39668183 Cosima M Schmid et al. ()
c.3170G>A p.Arg1057Gln missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1563G>A p.Gln521= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.353A>C p.Gln118Pro missense_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.707C>T p.Thr236Ile missense_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.2210-8T>C p.? splice_region_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1068+3A>G p.? splice_region_variant De novo - Unknown 39668183 Cosima M Schmid et al. ()
c.2209+1G>T p.? splice_site_variant Unknown - Multiplex 39668183 Cosima M Schmid et al. ()
c.1604dup p.Met535IlefsTer4 frameshift_variant De novo - - 32730804 Fliedner A et al. (2020)
c.1621C>G p.Pro541Ala missense_variant Unknown - Multiplex 39668183 Cosima M Schmid et al. ()
c.31-1G>A p.? splice_site_variant Familial Maternal Simplex 39668183 Cosima M Schmid et al. ()
c.983del p.Pro328HisfsTer3 frameshift_variant De novo - Simplex 32730804 Fliedner A et al. (2020)
c.2488+1G>A p.? splice_site_variant Familial Maternal Simplex 39668183 Cosima M Schmid et al. ()
c.1378C>T p.Arg460Ter stop_gained Familial Maternal Multiplex 39668183 Cosima M Schmid et al. ()
c.1276C>T p.Arg426Ter stop_gained Unknown Not maternal Simplex 39668183 Cosima M Schmid et al. ()
c.1339C>T p.Arg447Ter stop_gained Unknown Not maternal Simplex 39668183 Cosima M Schmid et al. ()
c.-250_1513+250del - copy_number_loss Familial Maternal Simplex 39668183 Cosima M Schmid et al. ()
c.521dup p.Ala176SerfsTer9 frameshift_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.158delT p.Lys53SerfsTer13 frameshift_variant Unknown - Unknown 39668183 Cosima M Schmid et al. ()
c.2682del p.Gly896AlafsTer10 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.1669dup p.Tyr557LeufsTer13 frameshift_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.2375del p.Ala792ValfsTer11 frameshift_variant Unknown - Simplex 39668183 Cosima M Schmid et al. ()
c.1889G>A p.Trp630Ter stop_gained Unknown Not maternal Multiplex 39668183 Cosima M Schmid et al. ()
c.408_411del p.Asn136LysfsTer8 frameshift_variant De novo - Simplex 32730804 Fliedner A et al. (2020)
c.1322G>C p.Arg441Thr missense_variant Unknown Not maternal Simplex 39668183 Cosima M Schmid et al. ()
c.836_839del p.Lys279ArgfsTer66 frameshift_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1295_1296del p.Arg432LysfsTer5 frameshift_variant De novo - Simplex 39668183 Cosima M Schmid et al. ()
c.1457_1458del p.Lys486ArgfsTer49 frameshift_variant Unknown - Unknown 39668183 Cosima M Schmid et al. ()
c.839_840del p.Glu280GlyfsTer82 frameshift_variant Unknown - Multiplex 39668183 Cosima M Schmid et al. ()
c.1064_1068+12del p.? splice_site_variant Unknown - Extended multiplex 39668183 Cosima M Schmid et al. ()
c.3155_3156del p.Glu1052ValfsTer3 frameshift_variant Unknown - Multiplex 32730804 Fliedner A et al. (2020)
c.768del p.Phe257LeufsTer89 frameshift_variant Familial Paternal Simplex 39668183 Cosima M Schmid et al. ()
c.2503dup p.Ala835GlyfsTer83 frameshift_variant Unknown Not maternal Simplex 39668183 Cosima M Schmid et al. ()
c.1746_1749del p.Asn582LysfsTer3 frameshift_variant Familial Maternal Simplex 39668183 Cosima M Schmid et al. ()
c.1463_1466del p.Arg488AsnfsTer10 frameshift_variant Familial Paternal Simplex 39668183 Cosima M Schmid et al. ()
c.1463_1466del p.Arg488AsnfsTer10 frameshift_variant Familial Paternal Multiplex 39668183 Cosima M Schmid et al. ()
c.299_302del p.Tyr100PhefsTer10 frameshift_variant De novo - Multiplex (monozygotic twins) 39668183 Cosima M Schmid et al. ()
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

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."

4/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.45169507805643

Ranking 10619/25841 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 0.99999969330117

Ranking 241/18225 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 0.83778935704464

Ranking 3067/18665 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 0.12669080185155

Ranking 5603/20870 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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