Human Gene Module / Chromosome 16 / TRAP1

TRAP1TNF receptor associated protein 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16p13.3
Associated Disorders
-
Relevance to Autism

Rydzanicz et al., 2024 reported a postzygotic mosaic nonsense variant in the TRAP1 gene (p.Gln639Ter) in an ASD proband from an ASD-discordant monozygotic twin pair; additional screening of 176 unrelated Polish ASD probands identified the same TRAP1 variant in a male patient who had inherited it from a healthy mother. Knock-in mice with the equivalent p.Gln641Ter mutation displayed ASD-related behavioral abnormalities that were more pronounced in males than in females, and this mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Inherited loss-of-function variants in the TRAP1 gene have previously been observed in individuals with ASD from four multiplex families from the AGRE cohort (Cirnigliaro et al., 2023).

Molecular Function

This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRAP1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Cirnigliaro M et al. (2023) Yes -
2 Support - Omri Bar et al. (2024) Yes -
3 Primary - Małgorzata Rydzanicz et al. (2024) Yes -
4 Support - Jesper Eisfeldt et al. (2024) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Paternal Simplex 39472019 Jesper Eisfeldt et al. (2024)
c.383G>A p.Arg128His missense_variant Familial Unknown Simplex 38256266 Omri Bar et al. (2024)
c.757A>G p.Ile253Val missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.1804C>T p.Arg602Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2107C>T p.Arg703Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1915C>T p.Gln639Ter stop_gained De novo - Simplex 39333440 Małgorzata Rydzanicz et al. (2024)
c.248-2A>G p.? splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1915C>T p.Gln639Ter stop_gained Familial Maternal Simplex 39333440 Małgorzata Rydzanicz et al. (2024)
c.1390A>G p.Ile464Val missense_variant Familial Paternal Unknown 39333440 Małgorzata Rydzanicz et al. (2024)
c.1418C>T p.Ser473Leu missense_variant Familial Maternal Unknown 39333440 Małgorzata Rydzanicz et al. (2024)
c.1753T>C p.Trp585Arg missense_variant Unknown Not maternal Unknown 39333440 Małgorzata Rydzanicz et al. (2024)
c.1990_1994del p.Leu664SerfsTer19 frameshift_variant Familial Maternal 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 0.13843433688481

Ranking 25721/25841 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 1.6203760478974E-17

Ranking 17851/18225 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 0.94593469661673

Ranking 16668/18665 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 0.216327344866

Ranking 3995/20870 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
CNVs associated with TRAP1(1 CNVs)
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16p13.3 71 Deletion-Duplication 101  /  542
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