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): 485 total — 33 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 128
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• 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: 19 — 11 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000382021, ENST00000506762, ENST00000509626, ENST00000512136, ENST00000642285, ENST00000642675, ENST00000642851, ENST00000644357, ENST00000646714, ENST00000648817, ENST00000698657, ENST00000698658, ENST00000698659, ENST00000698660, ENST00000698661, ENST00000911975, ENST00000911976, ENST00000966889, ENST00000966890

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.

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

256 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

180 targeting DNAJC21, 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-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

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)

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	Znf_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

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

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

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): 283, 302, 370, 511

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

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

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

900 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJC21	SBDS	Q9Y3A5	782
DNAJC21	EFL1	Q7Z2Z2	722
DNAJC21	SRP54	P13624	721
DNAJC21	HSPA4	P34932	691
DNAJC21	EIF6	P56537	679
DNAJC21	DNAJC24	Q6P3W2	669
DNAJC21	NMD3	Q96D46	665
DNAJC21	RSL24D1	Q9UHA3	603
DNAJC21	LSG1	Q9H089	568
DNAJC21	DNAJC6	O75061	561
DNAJC21	MRTO4	Q9UKD2	508
DNAJC21	DNAJC8	O75937	503
DNAJC21	GTPBP4	Q9BZE4	468
DNAJC21	JAGN1	Q8N5M9	465
DNAJC21	ZNF622	Q969S3	449

IntAct

39 interactions, top by confidence:

A	B	Type	Score
FTH1	NCOA4	psi-mi:“MI:0914”(association)	0.790
EZH2	EPOP	psi-mi:“MI:0914”(association)	0.730
DNAJC21	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
DNAJC21	CTCF	psi-mi:“MI:0915”(physical association)	0.400
DNAJC21	HSPB1	psi-mi:“MI:0915”(physical association)	0.370
HSPB1	DNAJC21	psi-mi:“MI:0915”(physical association)	0.370
DNAJC21	HTT	psi-mi:“MI:0915”(physical association)	0.370
HTT	DNAJC21	psi-mi:“MI:0915”(physical association)	0.370
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
NIPSNAP1	TNRC18	psi-mi:“MI:0914”(association)	0.350
Pabpc1	ZC3HAV1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
PRKAA2	PPP6C	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
DNAJC21	TOP2A	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
RACK1	RPS3A	psi-mi:“MI:0914”(association)	0.350
RPL19	RPS3A	psi-mi:“MI:0914”(association)	0.350
RPS16	MCRIP1	psi-mi:“MI:0914”(association)	0.350
SFPQ	YLPM1	psi-mi:“MI:0914”(association)	0.350
SRP14	EIF3F	psi-mi:“MI:0914”(association)	0.350
MRPS17	POLRMT	psi-mi:“MI:0914”(association)	0.350
MRPS18B	IGF2BP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): DNAJC21 (Affinity Capture-MS), DNAJC21 (Two-hybrid), GRPEL1 (Co-fractionation), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Synthetic Lethality), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-RNA), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS), DNAJC21 (Affinity Capture-MS)

ESM2 similar proteins: A0A0L0P4F8, A3KN83, A8XEA2, A9Q1D5, A9UL78, B2GUV7, G5EDG2, O17966, O36966, O95251, P04786, P07799, P0CL88, P0CL89, P11387, P30181, P30189, P41511, P41512, P93119, Q00313, Q04750, Q05D44, Q06698, Q07050, Q09475, Q23243, Q23541, Q27746, Q4IEV4, Q4P3S3, Q54RC3, Q54UU6, Q5BJL5, Q5F1R6, Q5F371, Q5SVQ0, Q5UQH6, Q61T02, Q689Z5

Diamond homologs: A0Q1R3, A1JJD6, A1KR91, A1WAR7, A3MA88, A5EYE5, A5F362, A5IIT4, A6LJ63, A6Q486, A9LZV9, B0JW23, B0VA24, B0VQ00, B1LCI2, B1ZUS0, B2I2G6, B2TLZ8, B2V2I6, B5ENA2, B7GV08, B7I2B2, B7IFE0, B7J7X8, B7KEJ8, B8DQW8, B9KAB9, B9MDJ8, C3LTA6, C5BQ32, E9Q8D0, O06431, O34242, O35723, O54946, O75190, O75953, O87778, O89114, P25685

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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
Formation of a pool of free 40S subunits	6	16.4×	2e-04
Peptide chain elongation	5	15.5×	6e-04
Viral mRNA Translation	5	15.5×	6e-04
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	5	15.3×	6e-04
L13a-mediated translational silencing of Ceruloplasmin expression	6	14.8×	2e-04
SRP-dependent cotranslational protein targeting to membrane	6	14.7×	2e-04
GTP hydrolysis and joining of the 60S ribosomal subunit	6	14.7×	2e-04
Selenocysteine synthesis	5	14.7×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
rhythmic process	5	27.3×	1e-04
cytoplasmic translation	6	24.1×	3e-05
translation	9	20.1×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	12
Uncertain significance	207
Likely benign	168
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028445	NM_001012339.3(DNAJC21):c.1224dup (p.Gly409fs)	Pathogenic
1339571	NM_001012339.3(DNAJC21):c.148C>T (p.Gln50Ter)	Pathogenic
1339573	NM_001012339.3(DNAJC21):c.643_644delinsTTT (p.Lys215fs)	Pathogenic
1394237	NM_001012339.3(DNAJC21):c.673G>T (p.Glu225Ter)	Pathogenic
1416298	NM_001012339.3(DNAJC21):c.1167_1170del (p.Lys389fs)	Pathogenic
1438629	NM_001012339.3(DNAJC21):c.436dup (p.Thr146fs)	Pathogenic
1452644	NM_001012339.3(DNAJC21):c.340del (p.Val114fs)	Pathogenic
1975265	NM_001012339.3(DNAJC21):c.800_801del (p.Glu267fs)	Pathogenic
2029407	NM_001012339.3(DNAJC21):c.679C>T (p.Gln227Ter)	Pathogenic
2029926	NM_001012339.3(DNAJC21):c.559G>T (p.Glu187Ter)	Pathogenic
2039339	NM_001012339.3(DNAJC21):c.1069del (p.Ser357fs)	Pathogenic
2088733	NM_001012339.3(DNAJC21):c.1155del (p.Lys385fs)	Pathogenic
2181302	NM_001012339.3(DNAJC21):c.314del (p.Lys105fs)	Pathogenic
222063	NM_001012339.3(DNAJC21):c.94C>G (p.Pro32Ala)	Pathogenic
222064	NM_001012339.3(DNAJC21):c.517C>T (p.Arg173Ter)	Pathogenic
222065	NM_001012339.3(DNAJC21):c.793G>T (p.Glu265Ter)	Pathogenic
2751121	NM_001012339.3(DNAJC21):c.648_649del (p.Arg216fs)	Pathogenic
2769968	NM_001012339.3(DNAJC21):c.965C>A (p.Ser322Ter)	Pathogenic
2807142	NM_001012339.3(DNAJC21):c.15T>G (p.Tyr5Ter)	Pathogenic
2809444	NM_001012339.3(DNAJC21):c.1171C>T (p.Gln391Ter)	Pathogenic
2816354	NM_001012339.3(DNAJC21):c.345del (p.Phe115fs)	Pathogenic
2974424	NM_001012339.3(DNAJC21):c.661C>T (p.Arg221Ter)	Pathogenic
3011755	NM_001012339.3(DNAJC21):c.805C>T (p.Gln269Ter)	Pathogenic
3065635	NM_001012339.3(DNAJC21):c.381delinsCTAGTGT (p.Leu127delinsPheTer)	Pathogenic
3572946	NM_001012339.3(DNAJC21):c.645_646del (p.Arg216fs)	Pathogenic
3630257	NM_001012339.3(DNAJC21):c.238G>T (p.Glu80Ter)	Pathogenic
3645245	NM_001012339.3(DNAJC21):c.564_568del (p.Asn188fs)	Pathogenic
3651165	NM_001012339.3(DNAJC21):c.736C>T (p.Gln246Ter)	Pathogenic
4280725	NM_001012339.3(DNAJC21):c.411del (p.Phe137fs)	Pathogenic
4765902	NM_001012339.3(DNAJC21):c.882dup (p.Asp295fs)	Pathogenic

SpliceAI

1787 predictions. Top by Δscore:

Variant	Effect	Δscore
5:34929912:CCCGG:C	donor_gain	1.0000
5:34929913:CCGG:C	donor_gain	1.0000
5:34929914:CGG:C	donor_gain	1.0000
5:34929914:CGGG:C	donor_loss	1.0000
5:34929915:GG:G	donor_gain	1.0000
5:34929915:GGG:G	donor_gain	1.0000
5:34929916:GG:G	donor_gain	1.0000
5:34929916:GGTA:G	donor_loss	1.0000
5:34929917:G:GG	donor_gain	1.0000
5:34933812:CA:C	acceptor_loss	1.0000
5:34933813:A:AG	acceptor_gain	1.0000
5:34933813:AGA:A	acceptor_loss	1.0000
5:34933814:G:GA	acceptor_loss	1.0000
5:34933814:G:GG	acceptor_gain	1.0000
5:34933899:A:T	donor_gain	1.0000
5:34933904:GCATG:G	donor_gain	1.0000
5:34933907:TGGTG:T	donor_loss	1.0000
5:34933908:GGT:G	donor_loss	1.0000
5:34933909:G:GG	donor_gain	1.0000
5:34933909:GTGAG:G	donor_loss	1.0000
5:34933910:TGAG:T	donor_loss	1.0000
5:34933911:GAGCA:G	donor_loss	1.0000
5:34935705:TTCA:T	acceptor_loss	1.0000
5:34935706:TCAG:T	acceptor_loss	1.0000
5:34935707:CAG:C	acceptor_loss	1.0000
5:34935708:A:AG	acceptor_gain	1.0000
5:34935708:A:AT	acceptor_loss	1.0000
5:34935708:AG:A	acceptor_gain	1.0000
5:34935709:G:GC	acceptor_gain	1.0000
5:34935709:GG:G	acceptor_gain	1.0000

AlphaMissense

3583 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:34929899:C:A	A27D	1.000
5:34929910:C:A	H31N	1.000
5:34929910:C:G	H31D	1.000
5:34929912:C:A	H31Q	1.000
5:34929912:C:G	H31Q	1.000
5:34933853:T:C	F46L	1.000
5:34933854:T:C	F46S	1.000
5:34933855:T:A	F46L	1.000
5:34933855:T:G	F46L	1.000
5:34935711:T:C	Y65H	1.000
5:34929886:T:G	Y23D	0.999
5:34929890:G:C	R24P	0.999
5:34929902:T:C	L28P	0.999
5:34929911:A:G	H31R	0.999
5:34933819:A:C	K34N	0.999
5:34933819:A:T	K34N	0.999
5:34933854:T:G	F46C	0.999
5:34933868:G:C	A51P	0.999
5:34933871:G:C	A52P	0.999
5:34933872:C:A	A52E	0.999
5:34933884:T:C	L56S	0.999
5:34933884:T:G	L56W	0.999
5:34933903:A:C	R62S	0.999
5:34933903:A:T	R62S	0.999
5:34935711:T:G	Y65D	0.999
5:34935712:A:G	Y65C	0.999
5:34935720:C:G	H68D	0.999
5:34937350:T:A	W155R	0.999
5:34937350:T:C	W155R	0.999
5:34937411:C:A	A175D	0.999

dbSNP variants (sampled 300 via entrez): RS1000095006 (5:34930280 C>A,T), RS1000098512 (5:34956539 T>A), RS1000234367 (5:34953240 T>C), RS1000256136 (5:34939896 A>G), RS1000329840 (5:34928682 T>G), RS1000437810 (5:34959387 A>G), RS1000530594 (5:34932513 A>G), RS1000538385 (5:34935156 T>A), RS1000623812 (5:34932160 C>A,T), RS1000687749 (5:34940950 T>C), RS1000741385 (5:34940617 A>G), RS1000809407 (5:34947448 G>A), RS1000840230 (5:34944338 C>T), RS1000891569 (5:34959047 T>G), RS1000931744 (5:34935521 G>A)

Disease associations

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

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
bone marrow failure syndrome 3	Definitive	AR

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

128 total (30 of 128 shown, 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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001520_17	Response to angiotensin II receptor blocker therapy	9.000000e-06
GCST009391_875	Metabolite levels	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006523	symmetrical dimethylarginine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

34 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
Arsenic	affects methylation	1
Cadmium	increases abundance, increases expression	1
Chenodeoxycholic Acid	decreases expression, affects cotreatment, increases expression	1
Deoxycholic Acid	decreases expression, affects cotreatment, increases expression	1
Diclofenac	affects expression	1
Doxorubicin	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	1
Glycocholic Acid	affects cotreatment, increases expression, decreases expression	1
Glycodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	1
Gold	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01529827	PHASE2	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	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT01966367	PHASE1/PHASE2	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