Human Gene Module / Chromosome 16 / TRAF7

TRAF7TNF receptor associated factor 7

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
49 / 0
EAGLE Score
3.5
Limited Learn More
Aliases
TRAF7, RFWD1,  RNF119
Associated Syndromes
-
Chromosome Band
16p13.3
Associated Disorders
ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Molecular Function

Tumor necrosis factor (TNF; see MIM 191160) receptor-associated factors, such as TRAF7, are signal transducers for members of the TNF receptor superfamily. This gene encodes a E3 ubiquitin ligase capable of auto-ubiquitination, following phosphorylation by MAP3K3, and potentiates MEKK3-mediated activation of the NF-kappa-B, JUN/AP1 and DDIT3 transcriptional regulators.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRAF7 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Recent Recommendation De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features Tokita MJ , et al. (2018) No Epilepsy/seizures, ASD
4 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Recent Recommendation Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7 Castilla-Vallmanya L et al. (2020) No ASD
7 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Yuan B et al. (2023) Yes -
10 Support - Spataro N et al. (2023) No -
Rare Variants   (49)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2010C>A p.Cys670Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.22C>T p.Arg8Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.95C>T p.Thr32Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1546C>T p.Leu516Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1570C>T p.Arg524Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1864G>A p.Asp622Asn missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1804G>A p.Val602Met missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.210G>A p.Pro70%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1873C>G p.Leu625Val missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.1111C>G p.Arg371Gly missense_variant De novo - - 29961569 Tokita MJ , et al. (2018)
c.1801A>G p.Thr601Ala missense_variant De novo - - 29961569 Tokita MJ , et al. (2018)
c.1964G>A p.Arg655Gln missense_variant De novo - - 29961569 Tokita MJ , et al. (2018)
c.348+11G>A - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1964G>A p.Arg655Gln missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.1790del p.Gly597AlafsTer37 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1964G>A p.Arg655Gln missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1036A>G p.Lys346Glu missense_variant De novo - Multiplex 29961569 Tokita MJ , et al. (2018)
c.1964G>A p.Arg655Gln missense_variant De novo - Multiplex 29961569 Tokita MJ , et al. (2018)
c.565C>T p.Arg189Trp missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1097C>T p.Ser366Phe missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1148A>C p.Gln383Pro missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1204C>G p.Leu402Val missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1211T>A p.Val404Asp missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1223G>A p.Gly408Asp missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1328T>G p.Leu443Arg missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1494G>T p.Lys498Asn missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1555C>T p.Leu519Phe missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1570C>T p.Arg524Trp missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1673C>A p.Ser558Tyr missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1673C>T p.Ser558Phe missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1708C>G p.His570Asp missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1849T>C p.Phe617Leu missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1850T>C p.Phe617Ser missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1873C>G p.Leu625Val missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1936G>C p.Val646Leu missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1964G>A p.Arg655Gln missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1964G>A p.Arg655Gln missense_variant Unknown - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1975G>T p.Gly659Trp missense_variant De novo - - 32376980 Castilla-Vallmanya L et al. (2020)
c.1136-36_1136-35insCCCCC - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1135+22_1135+23insCCCCCCCC - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1964G>A p.Arg655Gln missense_variant Unknown Not maternal Unknown 29961569 Tokita MJ , et al. (2018)
c.1570C>T p.Arg524Trp missense_variant Familial Maternal - 32376980 Castilla-Vallmanya L et al. (2020)
c.1135+34_1135+35insCCCCCCCCCGG - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.981C>A p.Asp327Glu missense_variant Unknown Not maternal - 32376980 Castilla-Vallmanya L et al. (2020)
c.1089C>A p.Asp363Glu missense_variant Unknown Not maternal - 32376980 Castilla-Vallmanya L et al. (2020)
c.1109C>T p.Ala370Val missense_variant Unknown Not maternal - 32376980 Castilla-Vallmanya L et al. (2020)
c.1885A>C p.Ser629Arg missense_variant Unknown Not maternal - 32376980 Castilla-Vallmanya L et al. (2020)
c.1851C>G p.Phe617Leu missense_variant Familial Maternal Multiplex 32376980 Castilla-Vallmanya L et al. (2020)
c.1777C>T p.Arg593Trp missense_variant De novo - Not simplex (positive family history) 22495311 Neale BM , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
3S
icon
1

Decreased from 3S to 1

10/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Reports Added
[Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF72020]
1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

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

Decreased from 4S to 4S

Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019]
7/1/2018
icon
4S

Increased from to 4S

Description

De novo missense variants in the TRAF7 gene were identified in ASD probands in two studies (Neale et al., 2012; Krumm et al., 2015). De novo missense variants in this gene were observed in seven unrelated individuals presenting with development delay, congenital anomalies, and dysmorphic features; one of these individuals also presented with severe autism (Tokita et al., 2018). The p.Arg655Gln missense variant, which was observed in the ASD proband from Krumm et al., 2015 and four individuals from Tokita et al., 2018, was experimentally shown to significantly reduce ERK1/2 phosphorylation.

Krishnan Probability Score

Score 0.42235712220684

Ranking 21105/25841 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 0.46064722803218

Ranking 5661/18225 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 0.7765068293899

Ranking 1855/18665 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 0.085534761812784

Ranking 6429/20870 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 TRAF7(1 CNVs)
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16p13.3 68 Deletion-Duplication 98  /  537
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