EXD1

Summary

EXD1 (exonuclease 3’-5’ domain containing 1, HGNC:28507) is a protein-coding gene on chromosome 15q15.1, encoding piRNA biogenesis protein EXD1 (Q8NHP7). RNA-binding component of the PET complex, a multiprotein complex required for the processing of piRNAs during spermatogenesis.

Predicted to enable RNA binding activity and protein homodimerization activity. Predicted to be involved in piRNA processing. Predicted to be located in P granule. Predicted to be part of PET complex.

Source: NCBI Gene 161829 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001286441

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28507
Approved symbol	EXD1
Name	exonuclease 3’-5’ domain containing 1
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC33637
Ensembl gene	ENSG00000178997
Ensembl biotype	protein_coding
Entrez	161829

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000314992, ENST00000458580, ENST00000558396, ENST00000558881, ENST00000559743

RefSeq mRNA: 3 — MANE Select: NM_001286441 NM_001286441, NM_001385036, NM_152596

CCDS: CCDS10072, CCDS66738

Canonical transcript exons

ENST00000458580 — 12 exons

Exon	Start	End
ENSE00001214821	41189937	41190128
ENSE00001214829	41191442	41191585
ENSE00001214838	41195775	41195855
ENSE00001214846	41195933	41196037
ENSE00001214852	41209501	41209587
ENSE00001214857	41215775	41215833
ENSE00001214868	41182728	41184593
ENSE00001214873	41216668	41216795
ENSE00002248320	41230479	41230757
ENSE00003461585	41226443	41226628
ENSE00003565714	41217097	41217154
ENSE00003636685	41219830	41219898

Expression profiles

Bgee: expression breadth broad, 73 present calls, max score 86.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0756 / max 39.2444, expressed in 14 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149522	0.0756	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	86.91	gold quality
sperm	CL:0000019	86.81	gold quality
left testis	UBERON:0004533	86.23	gold quality
testis	UBERON:0000473	84.63	gold quality
buccal mucosa cell	CL:0002336	84.52	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.11	gold quality
secondary oocyte	CL:0000655	66.72	gold quality
adult organism	UBERON:0007023	58.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	54.04	gold quality
spinal cord	UBERON:0002240	52.76	gold quality
lower lobe of lung	UBERON:0008949	50.34	silver quality
oocyte	CL:0000023	49.71	silver quality
prefrontal cortex	UBERON:0000451	49.12	gold quality
stromal cell of endometrium	CL:0002255	48.58	gold quality
lower esophagus mucosa	UBERON:0035834	45.81	silver quality
substantia nigra	UBERON:0002038	45.62	gold quality
granulocyte	CL:0000094	45.26	silver quality
bone marrow cell	CL:0002092	45.13	gold quality
midbrain	UBERON:0001891	44.90	gold quality
frontal cortex	UBERON:0001870	44.30	gold quality
Ammon’s horn	UBERON:0001954	43.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	43.66	gold quality
neocortex	UBERON:0001950	43.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
cerebral cortex	UBERON:0000956	43.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	42.88	gold quality
anterior cingulate cortex	UBERON:0009835	42.73	gold quality
bone marrow	UBERON:0002371	42.21	gold quality
hypothalamus	UBERON:0001898	42.10	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.35
E-CURD-7	no	119.03
E-ENAD-17	no	23.33

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting EXD1, 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-4262	100.00	73.26	3931
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-561-3P	99.64	70.90	3647

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exd1	ENSDARG00000098669
mus_musculus	Exd1	ENSMUSG00000048647
rattus_norvegicus	Exd1	ENSRNOG00000025360
drosophila_melanogaster	egl	FBGN0000562
caenorhabditis_elegans		WBGENE00015680

Paralogs (1): EXOSC10 (ENSG00000171824)

Protein

Protein identifiers

piRNA biogenesis protein EXD1 — Q8NHP7 (reviewed: Q8NHP7)

Alternative names: Exonuclease 3’-5’ domain-containing protein 1, Exonuclease 3’-5’ domain-like-containing protein 1, Inactive exonuclease EXD1

All UniProt accessions (2): Q8NHP7, H0YK66

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding component of the PET complex, a multiprotein complex required for the processing of piRNAs during spermatogenesis. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposable elements, preventing their mobilization, which is essential for the germline integrity. The PET complex is required during the secondary piRNAs metabolic process for the PIWIL2 slicing-triggered loading of PIWIL4 piRNAs. In the PET complex, EXD1 probably acts as an RNA adapter. EXD1 is an inactive exonuclease.

Subunit / interactions. Homodimer. Component of the PET complex, at least composed of EXD1, PIWIL2, TDRD12 and piRNAs.

Subcellular location. Cytoplasm.

Domain organisation. The 3’-5’ exonuclease domain lacks the conserved Asp-Glu-Asp-Asp (DEDD) residues that coordinates divalent ions essential for exonuclease activity.

Similarity. Belongs to the EXD1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NHP7-1	1	yes
Q8NHP7-2	2
Q8NHP7-3	3

RefSeq proteins (3): NP_001273370, NP_001371965, NP_689809 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002562	3’-5’_exonuclease_dom	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily
IPR052144	piRNA_biogenesis_EXD1	Family

Pfam: PF01612

UniProt features (7 total): splice variant 2, chain 1, domain 1, region of interest 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHP7-F1	65.03	0.42

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 91 (showing top): AP1_01, GOMF_NUCLEASE_ACTIVITY, LFA1_Q6, GGGTGGRR_PAX4_03, TGANTCA_AP1_C, NRF2_Q4, GOBP_PIRNA_PROCESSING, TGGNNNNNNKCCAR_UNKNOWN, GOMF_EXONUCLEASE_ACTIVITY, GOBP_MEIOTIC_CELL_CYCLE, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOCC_POLE_PLASM, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS

GO Biological Process (4): regulatory ncRNA-mediated gene silencing (GO:0031047), piRNA processing (GO:0034587), meiotic cell cycle (GO:0051321), nucleobase-containing compound metabolic process (GO:0006139)

GO Molecular Function (5): RNA binding (GO:0003723), protein homodimerization activity (GO:0042803), nucleic acid binding (GO:0003676), protein binding (GO:0005515), 3’-5’ exonuclease activity (GO:0008408)

GO Cellular Component (3): P granule (GO:0043186), PET complex (GO:1990923), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
negative regulation of gene expression	1
regulatory ncRNA processing	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
primary metabolic process	1
nucleic acid binding	1
identical protein binding	1
protein dimerization activity	1
exonuclease activity	1
cytoplasmic ribonucleoprotein granule	1
germ plasm	1
protein-containing complex	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXD1	TDRD12	Q587J7	910
EXD1	EXD2	Q9NVH0	685
EXD1	PIWIL4	Q7Z3Z4	640
EXD1	PIWIL2	Q8TC59	622
EXD1	PIWIL1	Q96J94	605
EXD1	TDRD9	Q8NDG6	589
EXD1	TDRKH	Q9Y2W6	578
EXD1	EXD3	Q8N9H8	570
EXD1	GTSF1	Q8WW33	546
EXD1	FKBP6	O75344	543
EXD1	TDRD5	Q8NAT2	541
EXD1	TDRD1	Q9BXT4	538
EXD1	MOV10L1	Q9BXT6	532
EXD1	ZNF782	Q6ZMW2	471
EXD1	ZNF462	Q96JM2	466

IntAct

8 interactions, top by confidence:

A	B	Type	Score
EML2	EXD1	psi-mi:“MI:0915”(physical association)	0.560
EXD1	EML2	psi-mi:“MI:0915”(physical association)	0.560
EXD1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
EML2	EXD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): EXD1 (Two-hybrid), EXD1 (Two-hybrid), HIST1H2BH (Proximity Label-MS), EXD1 (Affinity Capture-MS), EXD1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM98, A1L1H3, B2GUN4, B4F7C4, D2H3M0, E1BP74, E1BPH3, E1BZ85, E1C3S7, E2QTD3, O08715, O35618, O88850, O88884, P61590, P61591, P61592, P61593, P61594, P97432, Q14596, Q1L981, Q501R9, Q5IFK1, Q5RC94, Q5U5Q9, Q5VCS6, Q5XIN1, Q5XX13, Q7TT79, Q7ZYI3, Q80XI1, Q8BJ34, Q8BLK9, Q8BP86, Q8BUH8, Q8C267, Q8IW35, Q8N841, Q8NAT2

Diamond homologs: H9IUR0, Q0P3U3, Q17902, Q6NRD5, Q8CDF7, Q8NHP7, Q9VU31

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2166 predictions. Top by Δscore:

Variant	Effect	Δscore
15:41184594:C:CC	acceptor_gain	1.0000
15:41189932:CCTA:C	donor_loss	1.0000
15:41189934:TACCT:T	donor_loss	1.0000
15:41189936:C:A	donor_loss	1.0000
15:41191515:T:A	donor_gain	1.0000
15:41195763:C:A	donor_gain	1.0000
15:41195928:CTTA:C	donor_loss	1.0000
15:41195929:TTA:T	donor_loss	1.0000
15:41195930:TA:T	donor_loss	1.0000
15:41195931:A:AC	donor_gain	1.0000
15:41195932:C:CA	donor_loss	1.0000
15:41195932:C:CC	donor_gain	1.0000
15:41195932:CCTT:C	donor_gain	1.0000
15:41195993:C:CT	acceptor_gain	1.0000
15:41195993:C:T	acceptor_gain	1.0000
15:41209585:TAT:T	acceptor_gain	1.0000
15:41209587:TC:T	acceptor_loss	1.0000
15:41209588:C:CC	acceptor_gain	1.0000
15:41209588:C:T	acceptor_loss	1.0000
15:41209589:T:A	acceptor_loss	1.0000
15:41215769:ACTT:A	donor_loss	1.0000
15:41215770:CTT:C	donor_loss	1.0000
15:41215771:TTA:T	donor_loss	1.0000
15:41215772:TACCG:T	donor_loss	1.0000
15:41215773:A:AC	donor_gain	1.0000
15:41215773:ACC:A	donor_loss	1.0000
15:41215774:C:CC	donor_gain	1.0000
15:41215774:CCG:C	donor_gain	1.0000
15:41215834:C:CC	acceptor_gain	1.0000
15:41216848:C:CT	acceptor_gain	1.0000

AlphaMissense

3761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:41195933:C:A	K155N	0.998
15:41195933:C:G	K155N	0.998
15:41195784:A:C	F179L	0.997
15:41195784:A:T	F179L	0.997
15:41195786:A:G	F179L	0.997
15:41190040:C:G	R260P	0.996
15:41209509:A:G	W118R	0.996
15:41209509:A:T	W118R	0.996
15:41191565:A:C	F189L	0.995
15:41191565:A:T	F189L	0.995
15:41191567:A:G	F189L	0.995
15:41195821:A:G	L167P	0.995
15:41195935:T:C	K155E	0.995
15:41195821:A:T	L167H	0.994
15:41195979:A:G	F140S	0.994
15:41196006:T:A	D131V	0.994
15:41196006:T:G	D131A	0.994
15:41196009:A:G	F130S	0.994
15:41215784:A:C	F88L	0.994
15:41215784:A:T	F88L	0.994
15:41215786:A:G	F88L	0.994
15:41195785:A:G	F179S	0.993
15:41195854:A:T	V156D	0.993
15:41195967:A:T	L144H	0.993
15:41209555:A:C	S102R	0.993
15:41209555:A:T	S102R	0.993
15:41209557:T:G	S102R	0.993
15:41195782:T:A	D180V	0.992
15:41195782:T:G	D180A	0.992
15:41195788:A:T	V178D	0.992

dbSNP variants (sampled 300 via entrez): RS1000114497 (15:41191710 T>C), RS1000163484 (15:41190442 C>T), RS1000169695 (15:41196830 A>C), RS1000176898 (15:41217862 C>T), RS1000398413 (15:41185568 C>T), RS1000407298 (15:41229619 T>C), RS1000443808 (15:41227718 A>G), RS1000586188 (15:41204446 G>T), RS1000589553 (15:41193370 GC>G), RS1000647530 (15:41223926 C>T), RS1000770421 (15:41199588 TTG>T), RS1000773639 (15:41198140 C>G), RS1000883001 (15:41223234 C>T), RS1000895772 (15:41206140 TA>T), RS1000945980 (15:41216923 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004133_26	Ulcerative colitis	3.000000e-07
GCST007267_143	Systolic blood pressure	5.000000e-13
GCST007563_20	Allergic disease (asthma, hay fever or eczema)	4.000000e-08
GCST90002383_265	Hematocrit	8.000000e-12
GCST90020053_12	Frailty index	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004348	hematocrit
EFO:0009885	frailty measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
kojic acid	decreases expression	1
Acetaminophen	decreases expression	1
Arbutin	decreases expression	1
Endosulfan	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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