EXOSC5

Summary

EXOSC5 (exosome component 5, HGNC:24662) is a protein-coding gene on chromosome 19q13.2, encoding Exosome complex component RRP46 (Q9NQT4). Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. It is a common-essential gene (DepMap: required in 92.3% of cancer cell lines).

Predicted to enable RNA binding activity. Involved in DNA deamination; RNA processing; and mRNA catabolic process. Acts upstream of or within defense response to virus. Located in cytosol; euchromatin; and nuclear lumen. Part of exosome (RNase complex).

Source: NCBI Gene 56915 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar ataxia, brain abnormalities, and cardiac conduction defects (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 73 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 92.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_020158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24662
Approved symbol	EXOSC5
Name	exosome component 5
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	hRrp46p, Rrp46p, RRP46, RRP41B, MGC12901, p12B
Ensembl gene	ENSG00000077348
Ensembl biotype	protein_coding
OMIM	606492
Entrez	56915

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 2 retained_intron

ENST00000221233, ENST00000593523, ENST00000593771, ENST00000596905, ENST00000602129, ENST00000688768, ENST00000916935, ENST00000916936, ENST00000916937, ENST00000916938, ENST00000916939, ENST00000916940

RefSeq mRNA: 1 — MANE Select: NM_020158 NM_020158

CCDS: CCDS12580

Canonical transcript exons

ENST00000221233 — 6 exons

Exon	Start	End
ENSE00000550885	41391841	41391962
ENSE00000708419	41387514	41387603
ENSE00000708420	41389765	41389905
ENSE00000842445	41386374	41386725
ENSE00003213517	41397181	41397359
ENSE00003600642	41392867	41392980

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 92.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.6885 / max 150.3751, expressed in 1799 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181058	24.6885	1799

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	92.71	gold quality
mononuclear cell	CL:0000842	92.26	gold quality
leukocyte	CL:0000738	91.72	gold quality
gastrocnemius	UBERON:0001388	91.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.55	gold quality
lower esophagus mucosa	UBERON:0035834	90.38	gold quality
muscle of leg	UBERON:0001383	90.14	gold quality
body of pancreas	UBERON:0001150	89.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.85	gold quality
prefrontal cortex	UBERON:0000451	88.77	gold quality
right adrenal gland	UBERON:0001233	88.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.13	gold quality
cortical plate	UBERON:0005343	88.12	gold quality
skin of abdomen	UBERON:0001416	87.86	gold quality
skin of leg	UBERON:0001511	87.83	gold quality
granulocyte	CL:0000094	87.68	gold quality
apex of heart	UBERON:0002098	87.47	gold quality
left adrenal gland	UBERON:0001234	87.35	gold quality
left adrenal gland cortex	UBERON:0035825	87.30	gold quality
esophagus mucosa	UBERON:0002469	87.26	gold quality
mucosa of transverse colon	UBERON:0004991	87.04	gold quality
right adrenal gland cortex	UBERON:0035827	87.01	gold quality
muscle organ	UBERON:0001630	86.63	gold quality
anterior cingulate cortex	UBERON:0009835	86.27	gold quality
cingulate cortex	UBERON:0003027	86.12	gold quality
right lobe of liver	UBERON:0001114	86.00	gold quality
nucleus accumbens	UBERON:0001882	85.93	gold quality
right frontal lobe	UBERON:0002810	85.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.83	gold quality
adrenal cortex	UBERON:0001235	85.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	2515.07
E-MTAB-7008	yes	1955.98
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

10 targeting EXOSC5, 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-4481	100.00	66.42	1669
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4443	98.02	66.25	1928

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• association of hCsl4p with the exosome is mediated by protein-protein interactions with hRrp42p and hRrp46p (PMID:11812149)
• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• These results in our study indicates gene silencing of SOCS1 remarkably enhanced the cytotoxicity efficiency of CML28 DNA vaccine in DCs. (PMID:16815301)
• rAAV/CML28-transduced DCs vaccine may serve as a feasible approach for the treatment of CML28-associated cancers. (PMID:18157497)
• Results suggest that Rrp46 forms a homodimer separately from exosome complexes and, depending on species, is a structural component of the machinery that cleaves DNA during apoptosis. (PMID:20660080)
• Further, subcellular co-localization assay showed that the two proteins could co-localize in the cytoplasm of K562 cells, but WT1/CML28 complexes were not detected by using immunoprecipitation. (PMID:23392705)
• The roles of Prdx1 and Exosc5 in host defense mechanisms in HBV infection. (PMID:30567989)
• Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness. (PMID:32504085)
• Risk of sudden cardiac death in EXOSC5-related disease. (PMID:34089229)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc5	ENSDARG00000040557
mus_musculus	Exosc5	ENSMUSG00000061286
rattus_norvegicus	Exosc5	ENSRNOG00000020635
drosophila_melanogaster	Rrp46	FBGN0037815
caenorhabditis_elegans		WBGENE00000798

Paralogs (2): EXOSC4 (ENSG00000178896), EXOSC6 (ENSG00000223496)

Protein

Protein identifiers

Exosome complex component RRP46 — Q9NQT4 (reviewed: Q9NQT4)

Alternative names: Chronic myelogenous leukemia tumor antigen 28, Exosome component 5, Ribosomal RNA-processing protein 46, p12B

All UniProt accessions (4): Q9NQT4, M0R050, M0R102, M0R289

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding ‘pervasive’ transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3’ untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. In vitro, EXOSC5 does not bind or digest single-stranded RNA and binds to double-stranded DNA without detectable DNase activity.

Subunit / interactions. Homodimer. Component of the RNA exosome core complex (Exo-9), composed of EXOSC1, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7, EXOSC8 and EXOSC9; within the complex interacts with EXOSC3, EXOSC8, and EXOSC9. The catalytically inactive RNA exosome core complex (Exo-9) associates with the catalytic subunit EXOSC10/RRP6. Exo-9 may associate with DIS3 to form the nucleolar exosome complex, or DIS3L to form the cytoplasmic exosome complex. Exo-9 is formed by a hexameric base ring consisting of the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and a cap ring consisting of EXOSC1, EXOSC2 and EXOSC3. The RNA exosome complex associates with cofactors C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4. Interacts with GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Tissue specificity. Highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis.

Disease relevance. Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC) [MIM:619576] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development and speech delay that are observed in most patients. Disease manifestations are variable and include infantile-onset hypotonia, poor motor development, poor feeding and overall growth, and ataxic gait due to cerebellar ataxia. Additional variable features are dysarthria, nystagmus, variable ocular anomalies, spasticity, hyperreflexia, and non-specific dysmorphic features. Brain imaging shows cerebellar hypoplasia, often with brainstem hypoplasia, enlarged ventricles, delayed myelination, and thin corpus callosum. A significant number of patients develop cardiac conduction defects in childhood or adolescence. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RNase PH family.

RefSeq proteins (1): NP_064543* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001247	ExoRNase_PH_dom1	Domain
IPR015847	ExoRNase_PH_dom2	Domain
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027408	PNPase/RNase_PH_dom_sf	Homologous_superfamily
IPR036345	ExoRNase_PH_dom2_sf	Homologous_superfamily
IPR050080	RNase_PH	Family

Pfam: PF01138, PF03725

UniProt features (28 total): strand 11, sequence variant 6, helix 5, turn 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9G8M	ELECTRON MICROSCOPY	3.3
2NN6	X-RAY DIFFRACTION	3.35
9G8O	ELECTRON MICROSCOPY	3.4
6D6Q	ELECTRON MICROSCOPY	3.45
6D6R	ELECTRON MICROSCOPY	3.45
9G8N	ELECTRON MICROSCOPY	3.7
6H25	ELECTRON MICROSCOPY	3.8
9G8P	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQT4-F1	84.59	0.63

Functional residue map

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

Post-translational modifications (1): 20

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 294 (showing top): GOBP_RIBOSOME_BIOGENESIS, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_SNO_S_RNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, USF_C, GOBP_DNA_MODIFICATION, GOBP_RNA_SURVEILLANCE, GOBP_DEFENSE_RESPONSE_TO_VIRUS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, FISCHER_DREAM_TARGETS, GOMF_EXONUCLEASE_ACTIVITY

GO Biological Process (10): rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), mRNA catabolic process (GO:0006402), rRNA catabolic process (GO:0016075), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), defense response to virus (GO:0051607), nuclear mRNA surveillance (GO:0071028), poly(A)-dependent snoRNA 3’-end processing (GO:0071051)

GO Molecular Function (4): 3’-5’-RNA exonuclease activity (GO:0000175), DNA binding (GO:0003677), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (11): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nucleolar exosome (RNase complex) (GO:0101019), exoribonuclease complex (GO:1905354)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Regulation of mRNA stability by proteins that bind AU-rich elements	3
PERK regulates gene expression	1
Deadenylation-dependent mRNA decay	1
rRNA processing in the nucleus and cytosol	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	3
cellular anatomical structure	3
rRNA metabolic process	2
RNA catabolic process	2
nucleic acid binding	2
exosome (RNase complex)	2
cytoplasm	2
intracellular anatomical structure	2
RNA processing	1
ribosome biogenesis	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
negative regulation of gene expression	1
mRNA metabolic process	1
snRNA 3’-end processing	1
DNA modification	1
defense response	1
response to virus	1
nuclear-transcribed mRNA catabolic process	1
nuclear RNA surveillance	1
sno(s)RNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
binding	1
nucleus	1
nuclear protein-containing complex	1
exoribonuclease complex	1
chromatin	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
nuclear exosome (RNase complex)	1
nucleolus	1
catalytic complex	1

Protein interactions and networks

STRING

2485 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC5	EXOSC9	Q06265	999
EXOSC5	EXOSC7	Q15024	999
EXOSC5	EXOSC8	Q96B26	999
EXOSC5	EXOSC3	Q9NQT5	999
EXOSC5	EXOSC1	Q9Y3B2	999
EXOSC5	EXOSC6	Q5RKV6	992
EXOSC5	EXOSC4	Q9NPD3	991
EXOSC5	EXOSC2	Q13868	972
EXOSC5	EXOSC10	Q01780	949
EXOSC5	DIS3	Q9Y2L1	889
EXOSC5	C1D	Q13901	882
EXOSC5	SKIC2	Q15477	856
EXOSC5	ZC3HAV1	Q7Z2W4	817
EXOSC5	MPHOSPH6	Q99547	773
EXOSC5	MTREX	P42285	743

IntAct

313 interactions, top by confidence:

A	B	Type	Score
EXOSC5	EXOSC1	psi-mi:“MI:0915”(physical association)	0.970
EXOSC1	EXOSC5	psi-mi:“MI:0915”(physical association)	0.970
EXOSC8	EXOSC5	psi-mi:“MI:0915”(physical association)	0.950
EXOSC5	EXOSC8	psi-mi:“MI:0915”(physical association)	0.950
EXOSC5	Zc3hav1	psi-mi:“MI:0407”(direct interaction)	0.810
Zc3hav1	EXOSC5	psi-mi:“MI:0914”(association)	0.810
Zc3hav1	EXOSC5	psi-mi:“MI:0915”(physical association)	0.810
EXOSC5	Zc3hav1	psi-mi:“MI:0915”(physical association)	0.810
EXOSC1	EXOSC10	psi-mi:“MI:0915”(physical association)	0.810
IKZF3	EXOSC5	psi-mi:“MI:0915”(physical association)	0.780
EXOSC5	IKZF3	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (296): EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), EXOSC5 (Two-hybrid), TRIM54 (Two-hybrid), DOCK8 (Two-hybrid), EXOSC5 (Affinity Capture-MS), EXOSC5 (Affinity Capture-MS), EXOSC5 (Affinity Capture-MS)

ESM2 similar proteins: A0JN39, A2RVK7, B8BJ39, B8BM17, D2SW95, D2XV59, O00178, O08582, O80526, P11029, P11497, P23514, P42932, P50990, P53618, P59016, Q13085, Q15024, Q28559, Q28DS0, Q2KHU3, Q2QNG7, Q2QXR8, Q2QZ86, Q2RAK2, Q3ZCI9, Q4R4U1, Q4R5J0, Q5R5F8, Q5R8Q7, Q5RAP1, Q5RCW2, Q5SWU9, Q5XGS8, Q5ZIA5, Q6EE31, Q8IWZ6, Q8IX04, Q8JGT5, Q8K1R3

Diamond homologs: C5D9D5, G5EG59, O42894, Q8EQT7, Q9CRA8, Q9NQT4, A0RXU1, A1RST0, A1SGA2, A1WVN7, A2BKC0, A2RVK7, A3DCH7, A3MUP1, A4IME3, A4VGR8, A4WM67, A4XI64, A4XL64, A4Y0L7, A5GF91, A5WB10, A6TM00, A6TM05, A6VEE1, A8WQQ5, A8ZZ59, A9A5C9, A9B8G1, A9WEJ7, B0K3T4, B0KBM5, B0KQ94, B0RRB8, B1J4L4, B1Y978, B2FN86, B2V900, B3EAF2, B4RC48

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EXOSC5	“form complex”	Exosome_Complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA decay by 3’ to 5’ exoribonuclease	7	84.7×	1e-10
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	7	75.3×	1e-10
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	7	75.3×	1e-10
KSRP (KHSRP) binds and destabilizes mRNA	7	75.3×	1e-10
Nuclear RNA decay	14	73.2×	3e-21
ATF4 activates genes in response to endoplasmic reticulum stress	7	48.4×	3e-09
Major pathway of rRNA processing in the nucleolus and cytosol	13	13.6×	4e-10

GO biological processes:

GO term	Partners	Fold	FDR
maturation of 5.8S rRNA	5	70.2×	3e-07
rRNA catabolic process	5	66.1×	4e-07
RNA catabolic process	10	60.7×	2e-13
nuclear-transcribed mRNA catabolic process	5	51.1×	1e-06
RNA processing	12	35.0×	2e-13
morphogenesis of an epithelium	5	22.9×	7e-05
rRNA processing	10	18.9×	8e-09
intermediate filament organization	5	16.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	51
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1300245	NM_020158.4(EXOSC5):c.526-72_689del	Pathogenic
1300246	NM_020158.4(EXOSC5):c.617T>A (p.Leu206His)	Pathogenic
1300247	NM_020158.4(EXOSC5):c.87del (p.His30fs)	Pathogenic
3359747	NM_020158.4(EXOSC5):c.525+1G>A	Likely pathogenic

SpliceAI

1173 predictions. Top by Δscore:

Variant	Effect	Δscore
19:41387508:TGGTA:T	donor_loss	1.0000
19:41387509:GGTA:G	donor_loss	1.0000
19:41387510:GTAC:G	donor_loss	1.0000
19:41387511:TAC:T	donor_loss	1.0000
19:41387512:A:AG	donor_loss	1.0000
19:41387513:C:A	donor_loss	1.0000
19:41391809:T:TA	donor_gain	1.0000
19:41391960:CAC:C	acceptor_gain	1.0000
19:41391963:C:CA	acceptor_loss	1.0000
19:41391963:C:CC	acceptor_gain	1.0000
19:41391964:T:C	acceptor_loss	1.0000
19:41397175:TCTTA:T	donor_loss	1.0000
19:41397176:CTTA:C	donor_loss	1.0000
19:41397177:TTA:T	donor_loss	1.0000
19:41397178:TA:T	donor_loss	1.0000
19:41397179:ACCT:A	donor_loss	1.0000
19:41386724:AGCT:A	acceptor_loss	0.9900
19:41386726:C:CC	acceptor_gain	0.9900
19:41386726:C:CG	acceptor_loss	0.9900
19:41386727:T:G	acceptor_loss	0.9900
19:41387515:T:TA	donor_gain	0.9900
19:41387602:TCC:T	acceptor_loss	0.9900
19:41387603:CCTAG:C	acceptor_loss	0.9900
19:41387604:C:A	acceptor_loss	0.9900
19:41387605:T:C	acceptor_loss	0.9900
19:41389760:CCTA:C	donor_loss	0.9900
19:41389761:CTA:C	donor_loss	0.9900
19:41389762:TA:T	donor_loss	0.9900
19:41389764:C:CA	donor_loss	0.9900
19:41389914:C:CT	acceptor_gain	0.9900

AlphaMissense

1501 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:41392950:C:T	G60E	0.998
19:41389830:C:A	G154W	0.997
19:41389860:C:G	A144P	0.997
19:41392968:A:T	V54D	0.997
19:41397201:C:T	G43D	0.997
19:41389885:A:C	N135K	0.996
19:41389885:A:T	N135K	0.996
19:41389829:C:T	G154E	0.995
19:41392951:C:G	G60R	0.995
19:41392951:C:T	G60R	0.995
19:41392959:C:T	G57D	0.995
19:41391887:C:G	R113P	0.994
19:41391921:A:G	C102R	0.994
19:41397195:G:T	A45D	0.994
19:41397196:C:G	A45P	0.994
19:41397199:A:G	S44P	0.994
19:41386672:G:C	F223L	0.993
19:41386672:G:T	F223L	0.993
19:41386674:A:G	F223L	0.993
19:41387578:G:T	A184D	0.993
19:41389871:G:T	A140E	0.993
19:41389883:G:T	A136D	0.993
19:41389884:C:G	A136P	0.993
19:41389830:C:G	G154R	0.992
19:41389830:C:T	G154R	0.992
19:41391866:A:G	L120P	0.992
19:41391882:A:G	S115P	0.992
19:41391932:A:T	I98N	0.992
19:41392908:G:T	A74D	0.992
19:41392960:C:G	G57R	0.992

dbSNP variants (sampled 300 via entrez): RS1000697683 (19:41392345 G>A), RS1000711603 (19:41394278 C>A,T), RS1000747631 (19:41393832 C>G,T), RS1000806299 (19:41397712 C>T), RS1000891582 (19:41394959 G>A), RS1001539566 (19:41397307 C>A,T), RS1001823243 (19:41396695 T>C), RS1001870109 (19:41398390 G>A), RS1002220621 (19:41391605 A>G), RS1002241633 (19:41391029 C>G), RS1002271303 (19:41392653 CAGAG>C,CAG), RS1002273998 (19:41390738 T>G), RS1002338686 (19:41386855 G>A,C), RS1002674137 (19:41388322 A>C,G), RS1002909465 (19:41393616 G>A)

Disease associations

OMIM: gene MIM:606492 | disease phenotypes: MIM:619576

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar ataxia, brain abnormalities, and cardiac conduction defects	Strong	Autosomal recessive

Mondo (1): cerebellar ataxia, brain abnormalities, and cardiac conduction defects (MONDO:0859200)

Orphanet (1): Neurodevelopmental delay-hypotonia-cerebellar ataxia-cardiac conduction defects syndrome (Orphanet:641361)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000340	Sloping forehead
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000692	Tooth malposition
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001510	Growth delay

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90000025_568	Appendicular lean mass	4.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066390 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, affects cotreatment, increases abundance, increases expression (+1 more)	3
perfluorooctane sulfonic acid	increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Plant Extracts	affects cotreatment, decreases expression, increases expression	2
Rotenone	decreases expression	2
Cyclosporine	increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	decreases expression, increases expression, affects cotreatment	1
Decitabine	affects expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Cisplatin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651395	Binding	Binding affinity to human EXOSC5 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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