SMG6

Summary

SMG6 (SMG6 nonsense mediated mRNA decay factor, HGNC:17809) is a protein-coding gene on chromosome 17p13.3, encoding Telomerase-binding protein EST1A (Q86US8). Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. It is a common-essential gene (DepMap: required in 91.6% of cancer cell lines).

This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD. Alternatively spliced transcript variants encoding distinct protein isoforms have been described.

Source: NCBI Gene 23293 — RefSeq curated summary.

At a glance

• GWAS associations: 77
• Clinical variants (ClinVar): 273 total
• Cancer dependency (DepMap): dependent in 91.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_017575

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17809
Approved symbol	SMG6
Name	SMG6 nonsense mediated mRNA decay factor
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0732, SMG-6, EST1A
Ensembl gene	ENSG00000070366
Ensembl biotype	protein_coding
OMIM	610963
Entrez	23293

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000263073, ENST00000354901, ENST00000536871, ENST00000570606, ENST00000570659, ENST00000570668, ENST00000570756, ENST00000570874, ENST00000571442, ENST00000572205, ENST00000572369, ENST00000573153, ENST00000573166, ENST00000573827, ENST00000574501, ENST00000575176, ENST00000575338, ENST00000575454, ENST00000575663, ENST00000576218, ENST00000883972

RefSeq mRNA: 4 — MANE Select: NM_017575 NM_001256827, NM_001256828, NM_001282326, NM_017575

CCDS: CCDS11016, CCDS58498

Canonical transcript exons

ENST00000263073 — 19 exons

Exon	Start	End
ENSE00000947188	2172658	2172859
ENSE00001116079	2292871	2292977
ENSE00001116080	2297863	2298055
ENSE00001116081	2297243	2297353
ENSE00001116082	2292552	2292630
ENSE00001116083	2282647	2282859
ENSE00001116092	2283625	2283735
ENSE00001133693	2303633	2303785
ENSE00002675978	2059843	2061622
ENSE00002967159	2186663	2186831
ENSE00003474784	2244658	2244719
ENSE00003502051	2065468	2065679
ENSE00003515224	2236492	2236637
ENSE00003530785	2085725	2085901
ENSE00003550815	2188399	2188515
ENSE00003561567	2298906	2300664
ENSE00003631242	2068778	2068931
ENSE00003645806	2081810	2081956
ENSE00003656046	2065073	2065154

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 95.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2081 / max 288.7617, expressed in 1802 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163817	6.3048	1697
163815	3.9941	1607
163816	3.8994	1269
163814	0.8790	525
163806	0.7350	365
163802	0.5984	35
163810	0.4567	225
163813	0.3537	152
163803	0.2695	120
163804	0.2537	108

Top tissues by expression

272 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	95.43	gold quality
left ovary	UBERON:0002119	93.40	gold quality
right testis	UBERON:0004534	92.70	gold quality
right ovary	UBERON:0002118	92.68	gold quality
left testis	UBERON:0004533	92.47	gold quality
body of uterus	UBERON:0009853	92.42	gold quality
ventricular zone	UBERON:0003053	92.35	gold quality
lower esophagus mucosa	UBERON:0035834	92.05	gold quality
adenohypophysis	UBERON:0002196	91.96	gold quality
ganglionic eminence	UBERON:0004023	91.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.35	gold quality
right adrenal gland	UBERON:0001233	91.15	gold quality
right adrenal gland cortex	UBERON:0035827	90.94	gold quality
endocervix	UBERON:0000458	90.90	gold quality
cerebellar hemisphere	UBERON:0002245	90.88	gold quality
left adrenal gland	UBERON:0001234	90.84	gold quality
cerebellar cortex	UBERON:0002129	90.75	gold quality
right coronary artery	UBERON:0001625	90.73	gold quality
sural nerve	UBERON:0015488	90.61	gold quality
left uterine tube	UBERON:0001303	90.46	gold quality
lower esophagus	UBERON:0013473	90.45	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.44	gold quality
pituitary gland	UBERON:0000007	90.30	gold quality
left adrenal gland cortex	UBERON:0035825	90.23	gold quality
ectocervix	UBERON:0012249	90.15	gold quality
mucosa of stomach	UBERON:0001199	90.14	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.04	gold quality
testis	UBERON:0000473	89.94	gold quality
ovary	UBERON:0000992	89.91	gold quality
right uterine tube	UBERON:0001302	89.80	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
UPF1	Unknown

miRNA regulators (miRDB)

121 targeting SMG6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 91.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• associated with most or all active telomerase in HeLa cell extracts; overexpression of hEST1A induces anaphase bridges due to chromosome-end fusions, and telomeric DNA persists at the fusion points (PMID:12676087)
• Human EST1A is associated with most or all active telomerase and is involved either directly or indirectly in telomere elongation and telomere capping. (PMID:16820686)
• Structural properties of the PIN domain indicate its putative active center consisting of invariant acidic amino acid residues, which is similar to the active center of 5’ nucleases. (PMID:17557331)
• Report shows that hEST1A assembles specifically with telomerase in the context of the telomerase RNA (hTR)-hTERT ribonucleoprotein, through the high affinity of hEST1A for hTR and specific protein-protein contacts with hTERT. (PMID:17940095)
• Data show that SMG6 interacts directly with the EJC via two conserved EJC-binding motifs (EBMs). (PMID:20930030)
• The tricotetrapeptide repeat-containing domain within Est1A was sufficient for interaction with hTERT. (PMID:22011238)
• Consistent with involvement of SMG6 in the decay process full-length nonsense-containing beta-globin mRNA was increased and the Delta169 decay intermediate was decreased in cells knocked down for SMG6. (PMID:24086375)
• The study demonstrates that SMG5-SMG7 and SMG6 exhibit different and non-overlapping modes of UPF1 recognition, thus pointing at distinguished roles in integrating the complex nonsense-mediated mRNA decay interaction network. (PMID:25013172)
• SMG6 requires UPF1 and SMG1 for nonsense-mediated mRNA decay. (PMID:25053839)
• A preferred sequence motif spanning most SMG6 cleavage sites has been discovered by analysis of endogenous non-sense-mediated mRNA decay targets. (PMID:25429978)
• Transcriptome-wide identification of nonsense-mediated mRNA decay-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways. (PMID:27864472)
• Nonsense-mediated mRNA decay (NMD) substrates with PTCs undergo constitutive SMG6-dependent endocleavage, rather than SMG7-dependent exonucleolytic decay. In contrast, the turnover of NMD substrates containing upstream ORFs and long 3’ UTRs involves both SMG6- and SMG7-dependent endo- and exonucleolytic decay, respectively; extent to which SMG6 and SMG7 degrade NMD substrates is determined by the mRNA architecture. (PMID:28461625)
• SRR intronic variation inhibits expression of its neighboring SMG6 gene and protects against temporal lobe epilepsy. (PMID:29363864)
• Readthrough of stop codons under limiting ABCE1 concentration involves frameshifting and inhibits nonsense-mediated mRNA decay. (PMID:32941650)
• CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway. (PMID:35487895)
• Mechanism of circRNA_SMG6 mediating lung macrophage ECM degradation via miR-570-3p in microplastics-induced emphysema. (PMID:38685156)
• UPF1 helicase orchestrates mutually exclusive interactions with the SMG6 endonuclease and UPF2. (PMID:38709891)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	smg6	ENSDARG00000100481
mus_musculus	Smg6	ENSMUSG00000038290
rattus_norvegicus	Smg6	ENSRNOG00000003041
drosophila_melanogaster	Smg6	FBGN0039260
caenorhabditis_elegans		WBGENE00004884

Protein

Protein identifiers

Telomerase-binding protein EST1A — Q86US8 (reviewed: Q86US8)

Alternative names: Ever shorter telomeres 1A, Nonsense mediated mRNA decay factor SMG6, Smg-6 homolog, hSmg5/7a

All UniProt accessions (10): Q86US8, I3L176, I3L1W8, I3L355, I3L390, I3L3A9, I3L421, K7EKV2, K7ELM2, K7ENH7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. May have a general role in telomere regulation. Promotes in vitro the ability of TERT to elongate telomeres. Overexpression induces telomere uncapping, chromosomal end-to-end fusions (telomeric DNA persists at the fusion points) and did not perturb TRF2 telomeric localization. Binds to the single-stranded 5’-(GTGTGG)(4)GTGT-3’ telomeric DNA, but not to a telomerase RNA template component (TER). Plays a role in nonsense-mediated mRNA decay. Is thought to provide a link to the mRNA degradation machinery as it has endonuclease activity required to initiate NMD, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation. Degrades single-stranded RNA (ssRNA), but not ssDNA or dsRNA.

Subunit / interactions. May form homooligomers. Associated component of the telomerase holoenzyme complex. Interacts with TERT, independently of the telomerase RNA. Interacts with SMG1, SMG5, SMG7, UPF1, UPF2, UPF3B and the PP2A catalytic subunits. Also interacts with the exon junction complex (EJC) composed at least of CASC3, EIF4A3, MAGOH and RBM8A; required for the process of nonsense-mediated mRNA decay. Interacts with DHX34; the interaction is RNA-independent.

Subcellular location. Nucleus. Nucleolus. Chromosome. Telomere. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous.

Domain organisation. The PINc domain confers endonuclease activity and is expected to bind the catalytic metal ion.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86US8-1	1	yes
Q86US8-2	2
Q86US8-3	3

RefSeq proteins (3): NP_001243756, NP_001243757, NP_060045* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002716	PIN_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR018834	DNA/RNA-bd_Est1-type	Domain
IPR019458	Est1-like_N	Domain
IPR029060	PIN-like_dom_sf	Homologous_superfamily
IPR045153	Est1/Ebs1-like	Family

Pfam: PF10373, PF10374, PF13638

UniProt features (105 total): helix 35, strand 15, compositionally biased region 11, modified residue 10, region of interest 8, sequence variant 8, mutagenesis site 7, coiled-coil region 3, binding site 3, splice variant 3, chain 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2DOK	X-RAY DIFFRACTION	1.8
2HWW	X-RAY DIFFRACTION	1.8
2HWX	X-RAY DIFFRACTION	1.9
4UM2	X-RAY DIFFRACTION	2.1
8RXB	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86US8-F1	64.74	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 1251; 1353; 1392

Post-translational modifications (10): 203, 332, 406, 433, 471, 479, 484, 831, 870, 874

Mutagenesis-validated functional residues (7):

Position	Phenotype
46–52	alters interaction with the ejc. loss of interaction with the ejc; when associated with 140-e–e-146.
140–146	alters interaction with the ejc. loss of interaction with the ejc; when associated with 46-e–e-52.
1251	impaired nonsense-mediated rna decay.
1251	loss of endonuclease activity and nonsense-mediated rna decay; when associated with n-1392.
1353	abolishes rnase activity.
1392	impaired nonsense-mediated rna decay; when associated with a-1251.
1392	loss of endonuclease activity and nonsense-mediated rna decay; when associated with n-1251.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

MSigDB gene sets: 190 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, TGCGCANK_UNKNOWN, PID_TELOMERASE_PATHWAY, GOBP_TELOMERE_CAPPING, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, SP1_Q2_01, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NUCLEAR_TRANSPORT

GO Biological Process (6): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), mRNA export from nucleus (GO:0006406), regulation of telomere maintenance (GO:0032204), regulation of telomere maintenance via telomerase (GO:0032210), regulation of dephosphorylation (GO:0035303), negative regulation of telomere capping (GO:1904354)

GO Molecular Function (12): RNA binding (GO:0003723), RNA endonuclease activity (GO:0004521), hydrolase activity (GO:0016787), telomeric repeat DNA binding (GO:0042162), ribonucleoprotein complex binding (GO:0043021), metal ion binding (GO:0046872), telomerase RNA binding (GO:0070034), DNA polymerase binding (GO:0070182), DNA binding (GO:0003677), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), telomerase holoenzyme complex (GO:0005697), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), ciliary basal body (GO:0036064), chromosome (GO:0005694), exon-exon junction complex (GO:0035145)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nonsense-Mediated Decay (NMD)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleic acid binding	2
nuclear protein-containing complex	2
intracellular membraneless organelle	2
cellular anatomical structure	2
nuclear-transcribed mRNA catabolic process	1
RNA export from nucleus	1
gene expression	1
mRNA transport	1
telomere maintenance	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomere lengthening	1
regulation of DNA biosynthetic process	1
dephosphorylation	1
regulation of metabolic process	1
telomere capping	1
negative regulation of telomere maintenance	1
regulation of telomere capping	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity	1
sequence-specific DNA binding	1
protein-containing complex binding	1
cation binding	1
RNA binding	1
enzyme binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
catalytic complex	1
ribonucleoprotein complex	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
microtubule organizing center	1

Protein interactions and networks

STRING

1944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMG6	UPF1	Q92900	997
SMG6	SMG5	Q9UPR3	970
SMG6	UPF2	Q9HAU5	945
SMG6	SMG7	Q92540	941
SMG6	UPF3A	Q9H1J1	929
SMG6	SMG1	Q96Q15	921
SMG6	SULT1E1	P49888	893
SMG6	SMG9	Q9H0W8	879
SMG6	TERT	O14746	877
SMG6	SMG8	Q8ND04	876
SMG6	UPF3B	Q9BZI7	864
SMG6	XRN1	Q8IZH2	806
SMG6	EIF4A3	P38919	735
SMG6	YWHAZ	P29213	719
SMG6	PNRC2	Q9NPJ4	719

IntAct

54 interactions, top by confidence:

A	B	Type	Score
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
LPIN3	CSNK2A2	psi-mi:“MI:0914”(association)	0.640
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
MEOX2	SMG6	psi-mi:“MI:0915”(physical association)	0.560
SMG6	CASP6	psi-mi:“MI:0915”(physical association)	0.560
SMG6	HIP1	psi-mi:“MI:0915”(physical association)	0.560
SMG6	LAMP2	psi-mi:“MI:0915”(physical association)	0.560
SMG6	RAN	psi-mi:“MI:0915”(physical association)	0.560
SMG6	PRPF40A	psi-mi:“MI:0915”(physical association)	0.560
ORF	EIF3D	psi-mi:“MI:0914”(association)	0.560
HAO2	EIF4G3	psi-mi:“MI:0914”(association)	0.530
C2orf68	PIR	psi-mi:“MI:0914”(association)	0.530
SMG6	UPF1	psi-mi:“MI:0915”(physical association)	0.500
SMG6	PHB1	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
TERT	SMG6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (118): RBM8A (Affinity Capture-Western), UPF1 (Affinity Capture-Western), MAGOH (Affinity Capture-Western), PABPC1 (Affinity Capture-Western), SMG6 (Affinity Capture-Western), UPF3B (Affinity Capture-Western), SMG5 (Affinity Capture-Western), SMG7 (Affinity Capture-Western), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS), SMG6 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IZ84, A0A1L8H8C0, A0A1L8HFX9, A2RUV4, F1LP90, F5HSE3, O43310, O60237, O75167, O88453, P41110, P61406, Q12830, Q1LVF3, Q2HJG4, Q2PFD7, Q3TLH4, Q5RAK6, Q5ZMS6, Q66HC1, Q6A0A2, Q6NRP6, Q6NZL0, Q6P1U3, Q6PKG0, Q75N33, Q7TN02, Q7TPM1, Q7YZA2, Q7Z6E9, Q80TN7, Q80XI3, Q86UR5, Q86US8, Q8IVL0, Q8IVL1, Q8K0V4, Q8N4C8, Q90YL3, Q90YY5

Diamond homologs: A0A0R4IZ84, F1R7R1, P61406, Q5RAK6, Q86US8, Q92540, Q9FZ99, Q5RJH6, Q1LVF3, Q5T5J6, Q9DBQ9, Q9P7J1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

273 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	232
Likely benign	15
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

4771 predictions. Top by Δscore:

Variant	Effect	Δscore
17:2061618:CTCCT:C	acceptor_gain	1.0000
17:2061619:TCCT:T	acceptor_gain	1.0000
17:2061620:CCTC:C	acceptor_gain	1.0000
17:2061620:CCTCT:C	acceptor_loss	1.0000
17:2061621:CT:C	acceptor_gain	1.0000
17:2061622:TC:T	acceptor_loss	1.0000
17:2061623:C:CC	acceptor_gain	1.0000
17:2061624:T:A	acceptor_loss	1.0000
17:2065467:CCAG:C	donor_gain	1.0000
17:2065489:A:AC	donor_gain	1.0000
17:2065490:C:CC	donor_gain	1.0000
17:2065680:C:CC	acceptor_gain	1.0000
17:2068774:TCA:T	donor_loss	1.0000
17:2068776:A:AC	donor_gain	1.0000
17:2068777:C:CA	donor_gain	1.0000
17:2068777:CCG:C	donor_gain	1.0000
17:2068805:T:TA	donor_gain	1.0000
17:2068806:C:A	donor_gain	1.0000
17:2068928:CAGC:C	acceptor_gain	1.0000
17:2068930:GCC:G	acceptor_loss	1.0000
17:2081805:TTCAC:T	donor_loss	1.0000
17:2081806:TCAC:T	donor_loss	1.0000
17:2081808:ACCTG:A	donor_loss	1.0000
17:2081809:C:CT	donor_loss	1.0000
17:2081820:T:A	donor_gain	1.0000
17:2081963:G:C	acceptor_gain	1.0000
17:2081966:G:C	acceptor_gain	1.0000
17:2081966:G:GC	acceptor_gain	1.0000
17:2081973:C:T	acceptor_gain	1.0000
17:2081977:C:CT	acceptor_gain	1.0000

AlphaMissense

9306 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:2061509:A:G	W1415R	1.000
17:2061509:A:T	W1415R	1.000
17:2061517:A:G	F1412S	1.000
17:2061538:G:C	P1405R	1.000
17:2061538:G:T	P1405H	1.000
17:2061541:A:T	V1404D	1.000
17:2061556:G:T	A1399E	1.000
17:2061557:C:G	A1399P	1.000
17:2061558:C:A	K1398N	1.000
17:2061558:C:G	K1398N	1.000
17:2061560:T:C	K1398E	1.000
17:2061560:T:G	K1398Q	1.000
17:2061565:C:G	R1396P	1.000
17:2061568:A:G	L1395P	1.000
17:2061570:G:C	N1394K	1.000
17:2061570:G:T	N1394K	1.000
17:2061576:G:C	D1392E	1.000
17:2061576:G:T	D1392E	1.000
17:2061577:T:A	D1392V	1.000
17:2061577:T:C	D1392G	1.000
17:2061577:T:G	D1392A	1.000
17:2061578:C:G	D1392H	1.000
17:2061583:G:C	T1390R	1.000
17:2061583:G:T	T1390K	1.000
17:2061586:A:C	L1389W	1.000
17:2061586:A:G	L1389S	1.000
17:2061589:A:C	L1388R	1.000
17:2061589:A:G	L1388P	1.000
17:2061589:A:T	L1388Q	1.000
17:2061592:A:T	V1387E	1.000

dbSNP variants (sampled 300 via entrez): RS1000010819 (17:2095613 C>A,G), RS1000020564 (17:2117932 T>C), RS1000024204 (17:2280404 A>C), RS1000034998 (17:2263006 A>C), RS1000073456 (17:2059894 G>A), RS1000084627 (17:2142130 G>T), RS1000088293 (17:2198442 A>C,G), RS1000098907 (17:2138815 T>C), RS1000134641 (17:2186126 G>A), RS1000143173 (17:2157893 T>C), RS1000144294 (17:2150728 T>C), RS1000155614 (17:2150937 C>T), RS1000161873 (17:2225193 T>C), RS1000164216 (17:2118638 G>A), RS1000168512 (17:2196979 C>T)

Disease associations

OMIM: gene MIM:610963 | disease phenotypes: MIM:300004

GenCC curated gene-disease

Mondo (1): corpus callosum agenesis-abnormal genitalia syndrome (MONDO:0010224)

Orphanet (1): Corpus callosum agenesis-abnormal genitalia syndrome (Orphanet:2508)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

77 associations (top):

Study	Trait	p-value
GCST000442_1	Aortic root size	2.000000e-11
GCST000998_4	Coronary heart disease	1.000000e-09
GCST001674_5	Esophageal cancer (squamous cell)	2.000000e-11
GCST001820_9	Metabolite levels (5-HIAA)	3.000000e-06
GCST002289_19	Coronary artery disease	1.000000e-07
GCST002539_85	Schizophrenia	3.000000e-10
GCST002783_257	Body mass index	2.000000e-08
GCST002783_386	Body mass index	9.000000e-08
GCST002783_579	Body mass index	8.000000e-08
GCST003094_5	Mitral valve prolapse	2.000000e-08
GCST003116_44	Coronary artery disease	5.000000e-07
GCST003117_37	Myocardial infarction	3.000000e-06
GCST004521_272	Autism spectrum disorder or schizophrenia	7.000000e-10
GCST004603_246	Platelet count	3.000000e-22
GCST004607_68	Plateletcrit	5.000000e-33
GCST004610_149	White blood cell count	7.000000e-13
GCST004625_236	Monocyte count	2.000000e-10
GCST004787_64	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	6.000000e-08
GCST004904_186	Body mass index	6.000000e-11
GCST005170_1	Intraocular pressure	1.000000e-12
GCST005194_182	Coronary artery disease	5.000000e-07
GCST005194_183	Coronary artery disease	1.000000e-14
GCST005195_124	Coronary artery disease	4.000000e-17
GCST005580_294	Intraocular pressure	2.000000e-09
GCST005580_95	Intraocular pressure	6.000000e-11
GCST005795_6	Femoral neck bone mineral density	2.000000e-12
GCST006106_1	Forehead morphology	1.000000e-06
GCST006288_281	Heel bone mineral density	2.000000e-56
GCST006288_349	Heel bone mineral density	2.000000e-34
GCST006288_354	Heel bone mineral density	4.000000e-26

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0005132	5-HIAA measurement
EFO:0004340	body mass index
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0005091	monocyte count
EFO:0004695	intraocular pressure measurement
EFO:0007785	femoral neck bone mineral density
EFO:0009270	heel bone mineral density
EFO:0007585	Cannabis use
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007986	reticulocyte count
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004833	neutrophil count
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563110	Proud Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
manganese chloride	decreases expression, increases abundance	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases methylation, increases abundance	1
Amiodarone	increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	increases expression	1
Manganese	decreases expression, increases abundance	1
Polychlorinated Biphenyls	affects expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	decreases methylation	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Lactic Acid	increases expression	1
Particulate Matter	decreases methylation, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7HK	Ubigene HEK293T SMG6 KO	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.