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Table S3 - List of 489 Non-Synonymous and Frame-Shifting Variants Which Were Predicted to Be Damaging (X: Termination Codon)

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Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Seems to be the key enzyme in the formation of an RA gradient chr15:101427859,c.287G>A(E3) p.96,R>H 0 1 ALDH1A3 along the dorso-ventral axis during the early eye development and also in the development of the olfactory system. chr15:101436180,c.709G>A(E7) p.237,G>R 0 0.99 IRAK3 Interleukin-1 receptor-associated kinase 3, Inhibits chr12:66605329,c.357C>A(E4), p.119, Y>X (417) _ _ dissociation of IRAK1 and IRAK4 from the Toll- like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex. Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to PRKDC protect and align broken ends of DNA. May also chr8:48697705,c.11075C>T(E77), p.3692, W>X(406) _ _ act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c- Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect machanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation. Sodium channel protein type 2 subunit alpha, Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the SCN2A chr2:166245784 c.5468A>C(E27) p.1823,D>A 0.35 0.001 voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. Complement C4-A,Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is C4A chr6:31964321 c.3620T>C(E28) p.1207,V>A 0.14 0 responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. Dynein heavy chain 11, axonemal, Force generating protein of respiratory cilia. Produces DNAH11 force towards the minus ends of microtubules. chr7:21658769 c.4321C>T(E24) p.1441,R>W _ 0.655 Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. eIF-2-alpha kinase GCN2, Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation EIF2AK4 activation of specific mRNAs, such as the chr15:40284406 c.2662G>C(E17) p.888,D>H 0.28 0.33 transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity). Dynein regulatory complex protein 1, Key component of the nexin-dynein regulatory complex (N-DRC), essential for N-DRC integrity. Required for the assembly and regulation of CCDC164 chr2:26679362 c.2200G>A(E17) p.734,V>M 0.1 0.412 specific classes of inner dynein arm motors. May also function to restrict dynein-driven microtubule sliding, thus aiding in the generation of ciliary bending. Nephrocystin-4, Involved in the organization of apical junctions in kidney cells together with NPHP4 chr1:5987742 c.1408G>A(E11) p.470,R>W 0.09 0.742 NPHP1 and RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis. Plasma kallikrein,The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively KLKB1 charged surface. It also releases bradykinin from chr4:187171427 c.629C>A(E7) p.210,A>E 0.57 0.1 HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Septin-12, Filament-forming cytoskeletal GTPase SEPT-12 (By similarity). May play a role in cytokinesis chr16:4837574 c.73C>T(E2) p.25,E>K 0.1 0.019 (Potential). Myotubularin-related protein 2, Phosphatase that MTMR2 acts on lipids with a phosphoinositol headgroup. chr11:95568581 c.1589G>C(E18) p.530,A>G 0.19 0.171 Has phosphatase activity towards Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Nesprin-1,Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization. Component of SUN-protein- containing multivariate complexes also called LINC complexes which link the nucleoskeleton and cytoskeleton by providing versatile outer SYNE1 nuclear membrane attachment sites for chr6:152652051 c.13556T>C(E77) p.4519,N>S _ 0.919 cytoskeletal filaments. May be involved in the maintenance of nuclear organization and structural integrity. Connects nuclei to the cytoskeleton by interacting with the nuclear envelope and with F- actin in the cytoplasm. May be required for centrosome migration to the apical cell surface during early ciliogenesis. WD repeat-containing protein 35, Component of the IFT complex A (IFT-A), a complex required for WDR35 retrograde ciliary transport. Required for chr2:20166621 c.1058C>G(E10) p.353,R>P 0.01 0.365 ciliogenesis. May promote CASP3 activation and TNF-stimulated apoptosis. Vitamin K epoxide reductase complex subunit 1,nvolved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin VKORC1 K 2,3-epoxide to active vitamin K. Vitamin K is chr16:31104713 c.203T>C(E2) p.68,H>R 0.37 0.03 required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development. Dihydropyrimidine dehydrogenase [NADP(+)], Involved in pyrimidine base degradation. DPYD Catalyzes the reduction of uracil and thymine. chr1:97700547 c.2303G>T(E19) p.768,T>K 0.16 0.046 Also involved the degradation of the chemotherapeutic drug 5-fluorouracil. Table S3 - List of 489 non-synonymous and frame-shifting variants which were predicted to be damaging (X: termination codon). Gene Uniprot function Genome position (hg19) AA position & change SIFT Polyphen-2 USH2A Usherin,Involved in hearing and vision.
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