Human Gene Module / Chromosome 6 / COL12A1

COL12A1collagen type XII alpha 1 chain

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 8
Rare Variants / Common Variants
11 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
6q13-q14.1
Associated Disorders
-
Relevance to Autism

A de novo loss-of-function variant in the COL12A1 gene was identified in a Korean ASD proband in Kim et al., 2024; this gene was subsequently classifed as an ASD candidate gene in males following a combined TADA analysis consisting of the Korean ASD cohort described in Kim et al., 2024 in addition to the Simons Simplex Collection and the SPARK cohort. An additional de novo loss-of-function variant and four de novo missense variants in COL12A1 were reported in ASD probands from the SSC and SPARK cohorts, while an additional de novo missense variant in this gene was reported in an ASC proband (Iossifov et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). Inherited loss-of-function and missense variants in COL12A1 have also been identified in ASD probands (Ruzzo et al., 2019; Tuncay et al., 2023; Cirnigliaro et al., 2023).

Molecular Function

This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to COL12A1 (8 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 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Trost B et al. (2022) Yes -
6 Support - Tuncay IO et al. (2023) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
8 Primary - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1061G>A p.Trp354Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2939G>A p.Ser980Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3311G>A p.Arg1104Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2622G>T p.Lys874Asn missense_variant De novo - - 36368308 Trost B et al. (2022)
c.19C>G p.Pro7Ala missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2979_2983+9del p.? splice_site_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2714G>A p.Arg905His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1511T>C p.Ile504Thr missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.2726T>C p.Val909Ala missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.1288+2T>C p.? splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5665-2A>G p.? splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49460944316533

Ranking 3549/25841 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 0.99999961139933

Ranking 251/18225 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 0.92962269916031

Ranking 11215/18665 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 -0.093550229425698

Ranking 12120/20870 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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