DNAJC21

Summary

DNAJC21 (DnaJ heat shock protein family (Hsp40) member C21, HGNC:27030) is a protein-coding gene on chromosome 5p13.2, encoding DnaJ homolog subfamily C member 21 (Q5F1R6). May act as a co-chaperone for HSP70.

This gene encodes a member of the DNAJ heat shock protein 40 family of proteins that is characterized by two N-terminal tetratricopeptide repeat domains and a C-terminal DNAJ domain. This protein binds the precursor 45S ribosomal RNA and may be involved in early nuclear ribosomal RNA biogenesis and maturation of the 60S ribosomal subunit. Mutations in this gene result in Bone marrow failure syndrome 3. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 134218 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bone marrow failure syndrome 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 520 total — 31 pathogenic, 18 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 36 tissues, sQTL in 43 (q < 0.05)
• Phenotypes (HPO): 128
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.08 (unconstrained)
• MANE Select transcript: NM_001012339

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27030
Approved symbol	DNAJC21
Name	DnaJ heat shock protein family (Hsp40) member C21
Location	5p13.2
Locus type	gene with protein product
Status	Approved
Aliases	GS3, DNAJA5, JJJ1
Ensembl gene	ENSG00000168724
Ensembl biotype	protein_coding
OMIM	617048
Entrez	134218

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 16 protein_coding, 7 nonsense_mediated_decay, 6 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000648817

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 2: 4

ENST00000648817, ENST00000382021, ENST00000506762, ENST00000509626, ENST00000512136, ENST00000642285, ENST00000642675, ENST00000642851, ENST00000644357, ENST00000646714, ENST00000698657, ENST00000698658, ENST00000698659, ENST00000698660, ENST00000698661, ENST00000911975, ENST00000911976, ENST00000966889, ENST00000966890, ENST00000981420, ENST00000981421, ENST00000981422, ENST00001034801, ENST00001034803, ENST00001034804, ENST00001034805, ENST00001034807, ENST00001034808, ENST00001060306, ENST00001110243

RefSeq mRNA: 3 — MANE Select: NM_001012339 NM_001012339, NM_001348420, NM_194283

CCDS: CCDS34144, CCDS3907, CCDS87294

Canonical transcript exons

ENST00000648817 — 12 exons

Exon	Start	End
ENSE00001021414	34953926	34954001
ENSE00001490677	34936144	34936266
ENSE00001490679	34935710	34935833
ENSE00001490681	34933815	34933908
ENSE00001892355	34954553	34958964
ENSE00003533054	34938858	34939009
ENSE00003534359	34944867	34945025
ENSE00003561277	34937326	34937630
ENSE00003588494	34950170	34950342
ENSE00003665510	34945761	34945803
ENSE00003689947	34941096	34941183
ENSE00003833062	34929559	34929916

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.0171 / max 443.1959, expressed in 1821 samples.

Highest expression (Bgee): epithelial cell of pancreas, tibialis anterior, testis, deltoid, vastus lateralis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DNAJC21 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 43 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 79 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	5.1e-59	+0.81	5:34930271:T:C
Cells Cultured fibroblasts	sqtl	1.3e-54	+0.59	5:34945548:G:A
Testis	sqtl	1.5e-51	+1.03	5:34945548:G:A
Muscle Skeletal	sqtl	3.0e-48	+0.65	5:34945548:G:A
Artery Tibial	sqtl	3.9e-40	+0.67	5:34945548:G:A
Thyroid	sqtl	1.5e-37	+0.64	5:34945548:G:A
Nerve Tibial	sqtl	2.4e-35	+0.60	5:34945548:G:A
Adipose Subcutaneous	sqtl	2.6e-32	+0.57	5:34945548:G:A
Adipose Visceral Omentum	sqtl	4.6e-27	+0.59	5:34945548:G:A
Esophagus Mucosa	sqtl	7.0e-27	+0.54	5:34945548:G:A
Artery Aorta	sqtl	1.6e-24	+0.69	5:34945548:G:A
Cells EBV-transformed lymphocytes	eqtl	1.2e-22	+1.11	5:34930113:G:A
Artery Aorta	eqtl	1.6e-22	+0.48	5:34934012:G:A
Esophagus Muscularis	eqtl	1.8e-21	-0.17	5:34930282:T:C
Esophagus Muscularis	sqtl	1.8e-21	+0.56	5:34945548:G:A
Colon Transverse	sqtl	1.9e-21	+0.60	5:34945548:G:A
Thyroid	eqtl	2.0e-21	-0.26	5:34965160:G:A
Colon Sigmoid	sqtl	2.9e-21	+0.63	5:34945548:G:A
Cells EBV-transformed lymphocytes	sqtl	7.5e-21	+0.74	5:34945548:G:A
Adipose Subcutaneous	eqtl	1.6e-20	-0.22	5:34961375:T:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
56089	28.6242	1817
56088	4.2164	1608
56090	2.3014	1182
56091	0.8751	482

Top tissues by expression

showing 100 of 256 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	97.38	gold quality
tibialis anterior	UBERON:0001385	97.33	gold quality
left testis	UBERON:0004533	95.84	gold quality
deltoid	UBERON:0001476	95.55	gold quality
vastus lateralis	UBERON:0001379	95.31	gold quality
gastrocnemius	UBERON:0001388	95.31	gold quality
calcaneal tendon	UBERON:0003701	95.29	gold quality
muscle of leg	UBERON:0001383	95.20	gold quality
sperm	CL:0000019	95.19	gold quality
left ventricle myocardium	UBERON:0006566	95.16	gold quality
skeletal muscle tissue	UBERON:0001134	95.15	gold quality
right testis	UBERON:0004534	95.05	gold quality
quadriceps femoris	UBERON:0001377	95.04	gold quality
sural nerve	UBERON:0015488	95.03	gold quality
testis	UBERON:0000473	94.89	gold quality
muscle tissue	UBERON:0002385	94.77	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.67	gold quality
biceps brachii	UBERON:0001507	94.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.14	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.36	gold quality
islet of Langerhans	UBERON:0000006	93.20	gold quality
colonic epithelium	UBERON:0000397	92.96	gold quality
myocardium	UBERON:0002349	92.86	gold quality
cardiac atrium	UBERON:0002081	92.52	gold quality
right atrium auricular region	UBERON:0006631	92.50	gold quality
ectocervix	UBERON:0012249	92.48	gold quality
cauda epididymis	UBERON:0004360	92.23	gold quality
lower esophagus	UBERON:0013473	92.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.21	gold quality
endocervix	UBERON:0000458	92.19	gold quality
ileal mucosa	UBERON:0000331	92.16	gold quality
lower lobe of lung	UBERON:0008949	92.16	gold quality
uterine cervix	UBERON:0000002	92.07	gold quality
superficial temporal artery	UBERON:0001614	91.85	gold quality
popliteal artery	UBERON:0002250	91.84	gold quality
tibial artery	UBERON:0007610	91.83	gold quality
smooth muscle tissue	UBERON:0001135	91.82	gold quality
heart	UBERON:0000948	91.73	gold quality
pancreas	UBERON:0001264	91.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.71	gold quality
esophagus	UBERON:0001043	91.69	gold quality
heart left ventricle	UBERON:0002084	91.58	gold quality
tendon	UBERON:0000043	91.54	gold quality
lower esophagus mucosa	UBERON:0035834	91.49	gold quality
cardiac ventricle	UBERON:0002082	91.48	gold quality
gingival epithelium	UBERON:0001949	91.44	gold quality
descending thoracic aorta	UBERON:0002345	91.36	gold quality
aorta	UBERON:0000947	91.28	gold quality
right lung	UBERON:0002167	91.20	gold quality
esophagus mucosa	UBERON:0002469	91.18	gold quality
body of pancreas	UBERON:0001150	91.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.13	gold quality
vagina	UBERON:0000996	91.04	gold quality
heart right ventricle	UBERON:0002080	91.01	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.00	gold quality
amniotic fluid	UBERON:0000173	90.82	gold quality
rectum	UBERON:0001052	90.73	gold quality
stromal cell of endometrium	CL:0002255	90.67	gold quality
thoracic aorta	UBERON:0001515	90.63	gold quality
ascending aorta	UBERON:0001496	90.57	gold quality
monocyte	CL:0000576	90.53	gold quality
leukocyte	CL:0000738	90.49	gold quality
body of uterus	UBERON:0009853	90.43	gold quality
gingiva	UBERON:0001828	90.41	gold quality
left coronary artery	UBERON:0001626	90.36	gold quality
mucosa of stomach	UBERON:0001199	90.34	gold quality
tonsil	UBERON:0002372	90.30	gold quality
myometrium	UBERON:0001296	90.27	gold quality
minor salivary gland	UBERON:0001830	90.20	gold quality
uterus	UBERON:0000995	90.15	gold quality
caput epididymis	UBERON:0004358	90.12	gold quality
mouth mucosa	UBERON:0003729	90.01	gold quality
corpus epididymis	UBERON:0004359	89.98	gold quality
upper lobe of lung	UBERON:0008948	89.88	gold quality
lymph node	UBERON:0000029	89.85	gold quality
coronary artery	UBERON:0001621	89.84	gold quality
upper lobe of left lung	UBERON:0008952	89.82	gold quality
right coronary artery	UBERON:0001625	89.76	gold quality
vermiform appendix	UBERON:0001154	89.73	gold quality
endometrium	UBERON:0001295	89.70	gold quality
lung	UBERON:0002048	89.57	gold quality
gall bladder	UBERON:0002110	89.57	gold quality
tibial nerve	UBERON:0001323	89.56	gold quality
urinary bladder	UBERON:0001255	89.51	gold quality
female reproductive system	UBERON:0000474	89.38	gold quality
adult mammalian kidney	UBERON:0000082	89.28	gold quality
placenta	UBERON:0001987	89.25	gold quality
omental fat pad	UBERON:0010414	89.21	gold quality
peritoneum	UBERON:0002358	89.20	gold quality
adrenal tissue	UBERON:0018303	89.20	gold quality
colon	UBERON:0001155	89.18	gold quality
ventricular zone	UBERON:0003053	89.17	gold quality
body of stomach	UBERON:0001161	89.00	gold quality
large intestine	UBERON:0000059	88.91	gold quality
stomach	UBERON:0000945	88.84	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.82	gold quality
intestine	UBERON:0000160	88.73	gold quality
skin of abdomen	UBERON:0001416	88.71	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.47

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 72 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	82.9	medium
Testis	tissue	66.5	high
Tongue	tissue	48.4
Heart muscle	tissue	36.2	not detected
Midbrain	tissue	30.8
Pons	tissue	27.8
Cerebral cortex	tissue	26.1	high
Retrosplenial and cingulate cortex	tissue	26.1
Occipital cortex	tissue	25.1
Placenta	tissue	24.9	medium
Liver	tissue	24.5	high
Esophagus	tissue	24.3	medium
Somatosensory cortex	tissue	23.7
Kidney	tissue	23.2	medium
Bone marrow	tissue	23.0	not detected
Cervix	tissue	22.8	medium
Hypothalamus	tissue	22.6
Urinary bladder	tissue	22.1	medium
Stomach 1	tissue	19.7	high
Parathyroid gland	tissue	19.7	medium
Colon	tissue	19.7	high
Frontal cortex	tissue	19.7
Thalamus	tissue	19.7
Tonsil	tissue	19.6	medium
Smooth muscle	tissue	19.5	medium
Pancreas	tissue	19.3	high
Small intestine	tissue	19.2	high
Adipose tissue	tissue	19.0	not detected
Hippocampal formation	tissue	18.8
Thyroid gland	tissue	18.7	medium
Prostate	tissue	18.7	low
Lymph node	tissue	18.5	medium
Seminal vesicle	tissue	18.4	high
Rectum	tissue	18.3	high
Lung	tissue	18.3	low
Thymus	tissue	18.2
Duodenum	tissue	17.8	high
Salivary gland	tissue	17.5	high
Endometrium 1	tissue	16.5	medium
Entorhinal cortex	tissue	16.3
Postcentral gyrus	tissue	16.2
Appendix	tissue	15.9	medium
Choroid plexus	tissue	15.7
Medulla oblongata	tissue	15.2
Spinal cord	tissue	15.1
Adrenal gland	tissue	15.1	medium
Vagina	tissue	14.7	high
Breast	tissue	14.6	medium
Gallbladder	tissue	14.5	medium
Skin 1	tissue	14.4	high
Spleen	tissue	13.2	not detected
Epididymis	tissue	12.9	medium
Basal ganglia	tissue	12.5	medium
Septum	tissue	12.5
Substantia nigra	tissue	12.4
Ovary	tissue	12.2	not detected
Locus coeruleus	tissue	11.9
Cerebellum	tissue	11.4	not detected
Amygdala	tissue	11.3
Nucleus accumbens	tissue	10.8

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — Blood vessel (20.7), Paraventricular nucleus (15.2), Parvicellular reticular nuclei, medullary (15.2), Cervical spinal cord, ventral horn (15.1), Spinal trigeminal nucleus, interpolar (15.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting DNAJC21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 180 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
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-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834

Functional genomics

gnomAD constraint: pLI 1.03e-16, LOEUF 1.08, missense Z 0.306 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000648817 — one region, missense o/e 0.98. ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 5)

• molecular cloning (PMID:15067379)
• findings demonstrate that mutations in DNAJC21 cause a cancer-prone bone marrow failure syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit (PMID:27346687)
• Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. (PMID:28062395)
• We suggest that DNAJC21-related diseases constitute a distinct Inherited bone marrow failure syndromes (IBMFS) , with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations (PMID:29700810)
• Whole exome sequencing discloses heterozygous variants in the DNAJC21 and EFL1 genes but not in SRP54 in 6 out of 16 patients with Shwachman-Diamond Syndrome carrying biallelic SBDS mutations. (PMID:30198570)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnajc21	ENSDARG00000105195
mus_musculus	Dnajc21	ENSMUSG00000044224
rattus_norvegicus	Dnajc21	ENSRNOG00000017876
drosophila_melanogaster	CG2790	FBGN0027599
drosophila_melanogaster	Tpr2	FBGN0032586
drosophila_melanogaster	CG10565	FBGN0037051
drosophila_melanogaster	P58IPK	FBGN0037718
drosophila_melanogaster	l(3)80Fg	FBGN0287183
caenorhabditis_elegans		WBGENE00001020
caenorhabditis_elegans		WBGENE00001025
caenorhabditis_elegans		WBGENE00001026
caenorhabditis_elegans		WBGENE00001029
caenorhabditis_elegans		WBGENE00001035
caenorhabditis_elegans	dnj-28	WBGENE00001046
caenorhabditis_elegans		WBGENE00008122

Paralogs (20): DNAJC11 (ENSG00000007923), DNAJC25 (ENSG00000059769), DNAJC10 (ENSG00000077232), DNAJC5 (ENSG00000101152), DNAJC3 (ENSG00000102580), DNAJC17 (ENSG00000104129), DNAJC2 (ENSG00000105821), DNAJC12 (ENSG00000108176), DNAJC4 (ENSG00000110011), DNAJC16 (ENSG00000116138), DNAJC14 (ENSG00000135392), DNAJC1 (ENSG00000136770), DNAJC13 (ENSG00000138246), DNAJC5B (ENSG00000147570), DNAJC5G (ENSG00000163793), DNAJC7 (ENSG00000168259), DNAJC18 (ENSG00000170464), DNAJC24 (ENSG00000170946), DNAJC30 (ENSG00000176410), DNAJC9 (ENSG00000213551)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1925371) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
short tibia	1
abnormal sinus arrhythmia	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q95J56	98.9%	Diamond
Pongo abelii	Q5RBD7	98.2%	Diamond
Saccharomyces cerevisiae S288C	P53863	66.7%	Diamond
Nakaseomyces glabratus CBS 138	Q6FP17	60.6%	Diamond
Arabidopsis thaliana	Q9C911	52.8%	Diamond
Schizosaccharomyces pombe 972h-	O13601	51.6%	Diamond
Shewanella oneidensis MR-1	Q8EFW5	50.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
DNAJC21-AS1	ncRNA	124900961
PRLR	protein-coding	5618
AGXT2	protein-coding	64902
SPEF2	protein-coding	79925
TTC23L	protein-coding	153657
BRIX1	protein-coding	55299
RAD1	protein-coding	5810
TTC23L-AS1	ncRNA	101929704
RAI14-DT	ncRNA	105374723
RAI14	protein-coding	26064

Protein

Protein identifiers

DnaJ homolog subfamily C member 21 — Q5F1R6 (reviewed: Q5F1R6)

Alternative names: DnaJ homolog subfamily A member 5, Protein GS3

All UniProt accessions (6): Q5F1R6, A0A2R8Y4N5, A0A2R8Y4Q0, A0A2R8Y534, A0A2R8YET8, A0A8V8TNV5

UniProt curated annotations — full annotation on UniProt →

Function. May act as a co-chaperone for HSP70. May play a role in ribosomal RNA (rRNA) biogenesis, possibly in the maturation of the 60S subunit. Binds the precursor 45S rRNA.

Subunit / interactions. Interacts with HSPA8, PA2G4 and ZNF622.

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Tissue specificity. Expressed in brain, placenta, kidney and pancreas.

Disease relevance. Bone marrow failure syndrome 3 (BMFS3) [MIM:617052] A form of bone marrow failure syndrome, a heterogeneous group of life-threatening disorders characterized by hematopoietic defects in association with a range of variable extra-hematopoietic manifestations. BMFS3 is characterized by pancytopenia with onset in early childhood. Some patients have additional variable non-specific features, including poor growth, microcephaly, and skin anomalies. BMFS3 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5F1R6-1	1	yes
Q5F1R6-2	2
Q5F1R6-3	3

RefSeq proteins (3): NP_001012339, NP_001335349, NP_919259 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR003604	Matrin/U1-like-C_Znf_C2H2	Domain
IPR013087	Zf-C2H2_type	Domain
IPR018253	DnaJ_domain_CS	Conserved_site
IPR022755	Znf_C2H2_jaz	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily
IPR051964	Chaperone_stress_response	Family
IPR054076	ZUO1-like_ZHD	Domain

Pfam: PF00226, PF12171, PF21884

UniProt features (24 total): compositionally biased region 7, modified residue 4, sequence variant 3, region of interest 3, splice variant 2, zinc finger region 2, chain 1, domain 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5F1R6-F1	72.10	0.40

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoli

Antibody reliability (HPA): IH approved · IF supported

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 (4)

Type	Positions
Phosphoserine	283, 302, 370, 511

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 386 (showing top): GTACAGG_MIR486, CTCTAGA_MIR526C_MIR518F_MIR526A, GOBP_PROTEIN_MATURATION, CATTTCA_MIR203, GOBP_PROTEIN_FOLDING, YAMAZAKI_TCEB3_TARGETS_DN, BERENJENO_TRANSFORMED_BY_RHOA_UP, GOCC_RIBOSOME, ATGTACA_MIR493, GOCC_NUCLEOLUS, GINESTIER_BREAST_CANCER_20Q13_AMPLIFICATION_UP, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_WITH_LMP1_UP, KOYAMA_SEMA3B_TARGETS_DN, LEE_BMP2_TARGETS_DN, E2F1_UP.V1_UP

GO Biological Process (1): protein folding (GO:0006457)

GO Molecular Function (5): RNA binding (GO:0003723), zinc ion binding (GO:0008270), nucleic acid binding (GO:0003676), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), ribosome (GO:0005840), nucleus (GO:0005634)

GO top-level categories

12 GO namespaces:

Category	Terms
binding	2
intracellular membraneless organelle	2
cellular anatomical structure	2
cellular process	1
protein maturation	1
nucleic acid binding	1
transition metal ion binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
nucleolus	CC	direct assay
RNA binding	MF	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 964 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJC21	DNAJC24	Q6P3W2	887
DNAJC21	HSCB	Q8IWL3	824
DNAJC21	HSPA4	P34932	823
DNAJC21	SEC63	Q9UGP8	798
DNAJC21	DNAJC19	Q96DA6	798
DNAJC21	BLZF1	Q9H2G9	776
DNAJC21	SBDS	Q9Y3A5	772
DNAJC21	EFL1	Q7Z2Z2	765
DNAJC21	SRP54	P13624	749
DNAJC21	EIF6	P56537	691
DNAJC21	NMD3	Q96D46	565
DNAJC21	JAGN1	Q8N5M9	560
DNAJC21	RSL24D1	Q9UHA3	542
DNAJC21	DNAJC8	O75937	528
DNAJC21	ZNF622	Q969S3	503

IntAct

Human interaction partners of DNAJC21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
CTCF	physical association	0.400	1
H2BC9	physical association	0.400	1
HTT	physical association	0.370	6
HSPB1	physical association	0.370	2
TOP2A	association	0.350	1
MTERF1	physical association	0.000	2
VAV2	physical association	0.000	1

BioGRID (113 interactions; top human partners by supporting records): ATP5H (Cross-Linking-MS (XL-MS); 3 records), ESR1 (Affinity Capture-MS; 2 records), MRPS18B (Affinity Capture-MS; 2 records), TOP2A (Affinity Capture-MS; 2 records), AAMP (Co-fractionation), AGRN (Affinity Capture-MS), ANK2 (Affinity Capture-MS), ANLN (Affinity Capture-MS), ATG16L1 (Proximity Label-MS), ATP5A1 (Cross-Linking-MS (XL-MS)), BPIFA3 (Affinity Capture-MS), CACYBP (Proximity Label-MS), CAND1 (Affinity Capture-MS), CAPRIN1 (Co-fractionation), CAPZB (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for DNAJC21: 520 ClinVar records (49 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	18
Uncertain significance	219
Likely benign	184
Benign	3

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 49 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1028445	NM_001012339.3(DNAJC21):c.1224dup (p.Gly409fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1394237	NM_001012339.3(DNAJC21):c.673G>T (p.Glu225Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3572946	NM_001012339.3(DNAJC21):c.645_646del (p.Arg216fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2631314	NM_001012339.3(DNAJC21):c.895+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
617607	NM_001012339.3(DNAJC21):c.100A>G (p.Lys34Glu)	Pathogenic	criteria provided, single submitter	3
1339571	NM_001012339.3(DNAJC21):c.148C>T (p.Gln50Ter)	Pathogenic	criteria provided, single submitter	2
802111	NM_001012339.3(DNAJC21):c.982del (p.Ala328fs)	Pathogenic	criteria provided, single submitter	1
1416298	NM_001012339.3(DNAJC21):c.1167_1170del (p.Lys389fs)	Pathogenic	criteria provided, single submitter	1
1438629	NM_001012339.3(DNAJC21):c.436dup (p.Thr146fs)	Pathogenic	criteria provided, single submitter	1
1452644	NM_001012339.3(DNAJC21):c.340del (p.Val114fs)	Pathogenic	criteria provided, single submitter	1
1975265	NM_001012339.3(DNAJC21):c.800_801del (p.Glu267fs)	Pathogenic	criteria provided, single submitter	1
2029407	NM_001012339.3(DNAJC21):c.679C>T (p.Gln227Ter)	Pathogenic	criteria provided, single submitter	1
2029926	NM_001012339.3(DNAJC21):c.559G>T (p.Glu187Ter)	Pathogenic	criteria provided, single submitter	1
2039339	NM_001012339.3(DNAJC21):c.1069del (p.Ser357fs)	Pathogenic	criteria provided, single submitter	1
2088733	NM_001012339.3(DNAJC21):c.1155del (p.Lys385fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DNAJC21’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 973):

Position(s)	Effect	Δscore	Sites
5:34929917–34929918	donor_loss	1.0000	4
5:34933813–34933814	acceptor_loss	1.0000	6
5:34933899	donor_gain	1.0000
5:34933909–34933910	donor_loss	1.0000	6
5:34935708–34935709	acceptor_loss	1.0000	3
5:34935834–34935835	donor_loss	1.0000	4
5:34936134	acceptor_gain	1.0000
5:34936142	acceptor_loss	1.0000
5:34936143	acceptor_gain	1.0000
5:34936257	donor_gain	1.0000

AlphaMissense

1,140 missense substitutions predicted likely pathogenic (of 3,583 scored), across 271 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H31	8	0.997	1.000
D214	8	0.996	0.999
D33	8	0.993	0.998
F46	8	0.993	1.000
N188	8	0.991	0.998
H332	8	0.987	0.997
H338	8	0.985	0.995
D66	8	0.979	0.996
H500	8	0.977	0.993
H68	8	0.975	0.999
F151	8	0.969	0.995
F498	8	0.966	0.998
D58	8	0.965	0.995
H506	8	0.957	0.987
F115	8	0.955	0.988
F137	8	0.946	0.991
F107	8	0.940	0.996
M184	8	0.910	0.988
N35	8	0.909	0.990
F92	8	0.905	0.981

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.94e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.96e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000129

Disease associations

OMIM: gene MIM:617048 | disease phenotypes: MIM:617052, MIM:260400

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
bone marrow failure syndrome 3	Definitive	Autosomal recessive	4
Shwachman-Diamond syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
bone marrow failure syndrome 3	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
COVID-19 research	green
Cytopenia - NOT Fanconi anaemia	green
Cytopenias and congenital anaemias	green
Haematological malignancies cancer susceptibility	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Fetal anomalies	amber

Mondo (3): bone marrow failure syndrome 3 (MONDO:0014887), Shwachman-Diamond syndrome 1 (MONDO:0044204), Shwachman-Diamond syndrome (MONDO:0009833)

Orphanet (1): Shwachman-Diamond syndrome (Orphanet:811)

HPO phenotypes

showing 60 of 128 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000121	Nephrocalcinosis
HP:0000155	Oral ulcer
HP:0000246	Sinusitis
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000365	Hearing impairment
HP:0000378	Cupped ear
HP:0000483	Astigmatism
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000691	Microdontia
HP:0000705	Amelogenesis imperfecta
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000752	Hyperactivity
HP:0000774	Narrow chest
HP:0000819	Diabetes mellitus
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000886	Deformed rib cage
HP:0000907	Anterior rib cupping
HP:0000920	Enlargement of the costochondral junction
HP:0000924	Abnormality of the skeletal system
HP:0000938	Osteopenia
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001167	Abnormal finger morphology
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001328	Specific learning disability
HP:0001367	Abnormal joint morphology
HP:0001374	Congenital hip dislocation
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001627	Abnormal heart morphology
HP:0001700	Myocardial necrosis
HP:0001738	Exocrine pancreatic insufficiency
HP:0001792	Small nail
HP:0001871	Abnormality of blood and blood-forming tissues
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count

GWAS associations

2 associations:

Study	Trait	p-value
GCST009391_900	Metabolite levels	1e-6
GCST001520_17	Response to angiotensin II receptor blocker therapy	9e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0006523	symmetrical dimethylarginine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Carbamazepine	affects expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
clothianidin	increases expression	1
eprenetapopt	affects expression, affects reaction	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Chenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	1
Deoxycholic Acid	affects cotreatment, increases expression, decreases expression	1
Diclofenac	affects expression	1
Doxorubicin	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Glycochenodeoxycholic Acid	decreases expression, affects cotreatment, increases expression	1
Glycocholic Acid	increases expression, decreases expression, affects cotreatment	1
Glycodeoxycholic Acid	increases expression, decreases expression, affects cotreatment	1
Gold	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	increases expression, affects cotreatment	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

17 trials:

NCT	Phase	Status	Title
NCT00004787	Phase 2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01529827	Phase 2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	Phase 2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	Phase 2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01917708	Phase 1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	Phase 2/3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	Phase 2/3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT01966367	Phase 1/2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02011074	Not specified	COMPLETED	Perioperative Changes of Heart Rate Variability Related to Anxiety and Depressiveness in Patients Undergoing General Anesthesia
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT04275479	Not specified	TERMINATED	Diabetes/ Endocrine Surveillance in SDS
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06056908	Not specified	RECRUITING	Shwachman Diamond Syndrome Registry and Study
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform