Human Gene Module / Chromosome 16 / TERF2

TERF2Telomeric repeat binding factor 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
7 / 0
Aliases
TERF2, TRBF2,  TRF2
Associated Syndromes
-
Chromosome Band
16q22.1
Associated Disorders
-
Relevance to Autism

Two de novo variants (one splice-site, one missense) in the TERF2 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server.

Molecular Function

This gene encodes a telomere specific protein, TERF2, which is a component of the telomere nucleoprotein complex. This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length and plays a key role in the protective activity of telomeres.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TERF2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) No -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
4 Support - Mitani T et al. (2021) No -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Yuan B et al. (2023) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
8 Recent Recommendation - et al. () No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1382A>G p.Glu461Gly missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.858G>A p.Leu286%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1394G>A p.Trp465Ter stop_gained De novo - Simplex 34582790 Mitani T et al. (2021)
c.840+2T>C - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1332G>T p.Lys444Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1037C>A p.Ala346Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.523_524del p.Ile175GlnfsTer7 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants (one splice-site, one missense) in the TERF2 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value < 0.05), and no rare effect types were reported in the Exome Variant Server.

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo variants (one splice-site, one missense) in the TERF2 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value < 0.05), and no rare effect types were reported in the Exome Variant Server.

Reports Added
[New Scoring Scheme]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants (one splice-site, one missense) in the TERF2 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
icon
3

Increased from to 3

Description

Two de novo variants (one splice-site, one missense) in the TERF2 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server.

Krishnan Probability Score

Score 0.44728891034137

Ranking 12974/25841 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 0.92747217744859

Ranking 2956/18225 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
Iossifov Probability Score

Score 0.853

Ranking 190/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.49040285157598

Ranking 428/18665 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 0.52717014701798

Ranking 343/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Borcs7 BLOC-1 related complex subunit 7 Rat RNA Binding 294012 D3ZLX2
C1ql1 complement component 1, q subcomponent-like 1 Rat RNA Binding 363686 D3ZEN8
Camk2n2 calcium/calmodulin-dependent protein kinase II inhibitor 2 Rat RNA Binding 59314 Q9Z2N6
Ccdc125 coiled-coil domain containing 125 Rat RNA Binding 499518 F1LRT4
Cyp46a1 cytochrome P450, family 46, subfamily a, polypeptide 1 Rat RNA Binding 362782 F7EN52
Efna2 ephrin A2 Rat RNA Binding 84358 F1MA19
Fam57b family with sequence similarity 57, member B Rat RNA Binding 293493 B1WBX0
Gcfc2 GC-rich sequence DNA-binding factor 2 Rat RNA Binding 312474 D4A3Z4
Gtf2h5 general transcription factor IIH subunit 5 Rat RNA Binding 502227 D3ZEI7
HEXA Beta-hexosaminidase subunit alpha Human Protein Binding 3073 P06865
Il17d interleukin 17D Rat RNA Binding 691799
LOC103690796 60S ribosomal protein L9-like Rat RNA Binding 103690796
LOC301444 pseudogene for diazepam binding inhibitor 1 Rat RNA Binding 301444
LOC306766 hypothetical LOC306766 Rat RNA Binding 306766 Q5U2R6
LOC501280 similar to myosin regulatory light chain-like Rat RNA Binding 501280
LOC681314 similar to BAX protein, cytoplasmic isoform delta Rat RNA Binding 681314
LOC685668 hypothetical protein LOC685668 Rat RNA Binding 685668
Lrrc73 leucine rich repeat containing 73 Rat RNA Binding 501101 Q587K4
Ly6h lymphocyte antigen 6 complex, locus H Rat RNA Binding 300025 F1LNW6
Lypla2 lysophospholipase II Rat RNA Binding 83510 Q9QYL8
Mfap2 microfibrillar-associated protein 2 Rat RNA Binding 313662 D3Z952
Mlph melanophilin Rat RNA Binding 316620 G3V8M0
RGD1560015 similar to glycoprotein, synaptic 2 Rat RNA Binding 499018
RGD1564447 similar to Zgc:56193 Rat RNA Binding 367254 A0A0G2K5X7
RGD1564450 RGD1564450 Rat RNA Binding 294291
RGD1565784 RGD1565784 Rat RNA Binding 497874 D4ACY1
S100a1 S100 calcium binding protein A1 Rat RNA Binding 295214 P35467
Slc39a2 solute carrier family 39 (zinc transporter), member 2 Rat RNA Binding 305846 D3ZIN1
Spc25 SPC25, NDC80 kinetochore complex component Rat RNA Binding 295661 Q5M856
Tmem158 transmembrane protein 158 Rat RNA Binding 117582 Q91XV7
Zfp513 zinc finger protein 513 Rat RNA Binding 313913 Q5FWU5
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