Human Gene Module / Chromosome 7 / COL28A1

COL28A1collagen type XXVIII alpha 1 chain

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
34 / 0
Aliases
COL28A1, COL28
Associated Syndromes
-
Chromosome Band
7p21.3
Associated Disorders
-
Relevance to Autism

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Molecular Function

COL28A1 belongs to a class of collagens containing von Willebrand factor (VWF; MIM 613160) type A (VWFA) domains and may act as a cell-binding protein.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to COL28A1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
2 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1096-1G>A - splice_site_variant Familial - - 28831199 Li J , et al. (2017)
c.1791+1G>T - splice_site_variant Familial - - 28831199 Li J , et al. (2017)
c.1474C>T p.Arg492Ter stop_gained Familial - - 28831199 Li J , et al. (2017)
c.2165G>A p.Gly722Asp missense_variant Familial - - 28831199 Li J , et al. (2017)
c.1286C>G p.Ser429Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.2006C>T p.Pro669Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2940T>G p.Ile980Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
C>A p.Glu755Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
C>A p.Glu755Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2684dup p.Val898SerfsTer7 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.989del p.Pro330GlnfsTer108 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.124+2T>A - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.124+2T>A - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
G>A p.Pro515Leu missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
G>A p.Pro515Leu missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1929+2T>C - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2263G>T p.Glu755Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2263G>T p.Glu755Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2293C>T p.Gln765Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2293C>T p.Gln765Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.814-2A>T - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.202A>G p.Lys68Glu missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.305T>C p.Val102Ala missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.305T>C p.Val102Ala missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1210G>A p.Gly404Arg missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1544C>T p.Pro515Leu missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1544C>T p.Pro515Leu missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2165G>A p.Gly722Asp missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2356T>A p.Cys786Ser missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2293C>T p.Gln765Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1307del p.Asp436ValfsTer2 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1307del p.Asp436ValfsTer2 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2684dup p.Val898SerfsTer7 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2293C>T p.Gln765Ter stop_gained Familial Maternal Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
icon
4

Increased from to 4

Description

Rare inherited loss-of-function and damaging missense variants in the COL28A1 gene were identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a cohort of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified the COL28A1 gene as an ASD candidate gene with a PTADA between 0.005 and 0.01 (0.004605); however, PTADA for this gene failed to reach significance (P < 0.01) following TADA analysis using a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Krishnan Probability Score

Score 0.49162286403615

Ranking 5333/25841 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 1.8930347556404E-20

Ranking 17994/18225 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 0.94800563149548

Ranking 17507/18665 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
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