EFL1

Summary

EFL1 (elongation factor like GTPase 1, HGNC:25789) is a protein-coding gene on chromosome 15q25.2, encoding Elongation factor-like GTPase 1 (Q7Z2Z2). GTPase involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. It is a common-essential gene (DepMap: required in 95.9% of cancer cell lines).

Enables GTPase activity and ribosome binding activity. Involved in GTP metabolic process and cytosolic ribosome assembly. Predicted to be part of ribonucleoprotein complex. Predicted to be active in cytosol. Implicated in Shwachman-Diamond syndrome.

Source: NCBI Gene 79631 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Shwachman-Diamond syndrome 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 591 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 89
• Cancer dependency (DepMap): dependent in 95.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_024580

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25789
Approved symbol	EFL1
Name	elongation factor like GTPase 1
Location	15q25.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13119, FAM42A, HsT19294, RIA1
Ensembl gene	ENSG00000140598
Ensembl biotype	protein_coding
OMIM	617538
Entrez	79631

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000268206, ENST00000359445, ENST00000557844, ENST00000557939, ENST00000558974, ENST00000559429, ENST00000560095, ENST00000561331, ENST00000561340, ENST00000561389, ENST00000650113, ENST00000696327, ENST00000696329, ENST00000696330, ENST00000696335, ENST00000696336, ENST00000696337, ENST00000882433, ENST00000882434, ENST00000912650, ENST00000912651, ENST00000956175, ENST00000956176

RefSeq mRNA: 4 — MANE Select: NM_024580 NM_001040610, NM_001322844, NM_001322845, NM_024580

CCDS: CCDS42070, CCDS42071

Canonical transcript exons

ENST00000268206 — 20 exons

Exon	Start	End
ENSE00002564911	82151465	82152423
ENSE00002573677	82262614	82262734
ENSE00003786417	82261688	82261797
ENSE00003966881	82138658	82138842
ENSE00003967032	82214717	82214855
ENSE00003967033	82240418	82240555
ENSE00003967034	82241270	82241403
ENSE00003967035	82252691	82252775
ENSE00003967036	82157713	82157860
ENSE00003967037	82227450	82227572
ENSE00003967038	82238307	82238521
ENSE00003967039	82229034	82229110
ENSE00003967040	82219652	82219818
ENSE00003967042	82259088	82259155
ENSE00003967043	82220078	82220229
ENSE00003967044	82163853	82163984
ENSE00003967045	82228191	82228327
ENSE00003967046	82230848	82230971
ENSE00003967047	82225165	82225264
ENSE00003967079	82130233	82130561

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 93.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3436 / max 100.8505, expressed in 1764 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151246	11.3436	1764

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.18	gold quality
oocyte	CL:0000023	91.48	gold quality
ventricular zone	UBERON:0003053	90.05	gold quality
calcaneal tendon	UBERON:0003701	90.05	gold quality
colonic epithelium	UBERON:0000397	89.41	gold quality
cortical plate	UBERON:0005343	89.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.96	gold quality
rectum	UBERON:0001052	87.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.68	gold quality
islet of Langerhans	UBERON:0000006	87.58	gold quality
ganglionic eminence	UBERON:0004023	87.47	gold quality
embryo	UBERON:0000922	86.97	gold quality
mucosa of transverse colon	UBERON:0004991	86.13	gold quality
jejunal mucosa	UBERON:0000399	84.65	gold quality
bone marrow cell	CL:0002092	84.26	gold quality
decidua	UBERON:0002450	83.55	gold quality
stromal cell of endometrium	CL:0002255	83.43	gold quality
tibialis anterior	UBERON:0001385	83.34	gold quality
muscle of leg	UBERON:0001383	83.25	gold quality
gastrocnemius	UBERON:0001388	83.22	gold quality
tendon	UBERON:0000043	83.14	gold quality
ileal mucosa	UBERON:0000331	83.07	gold quality
monocyte	CL:0000576	83.01	gold quality
leukocyte	CL:0000738	82.89	gold quality
mononuclear cell	CL:0000842	82.85	gold quality
sperm	CL:0000019	82.70	silver quality
adrenal tissue	UBERON:0018303	82.43	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.34	gold quality
cartilage tissue	UBERON:0002418	82.14	gold quality
colonic mucosa	UBERON:0000317	82.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting EFL1, 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-651-3P	99.94	73.48	5177
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-4780	98.57	64.75	611
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-5196-3P	97.57	65.98	979

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 95.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• Downregulation of EFTUD1 induced cell-cycle arrest and apoptosis in gliomas by impairing ribosome biogenesis (PMID:25015090)
• Association of Elongation Factor-like 1 (EFL1) GTPase to SBDS did not modify the affinity for GTP but dramatically decreased that for GDP by increasing the dissociation rate of the nucleotide. (PMID:25991726)
• Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. (PMID:26479198)
• Mutations in EFL1 clinically manifest phenotypes of infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies. Mutant EFL1 proteins do not promote the release of yeast cytoplasmic Tif6 from the 60S subunit, likely preventing the formation of mature ribosomes. (PMID:28331068)
• 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)
• the effect of SBDS mutations on the interaction with EFL1were tested, and showed that all tested mutations disrupted the binding to EFL1. (PMID:30545121)
• we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. (PMID:31151987)
• Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics. (PMID:31838967)
• Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome. (PMID:34115847)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	efl1	ENSDARG00000079672
		ENSDARG00000117086
mus_musculus	Efl1	ENSMUSG00000038563
rattus_norvegicus	Efl1	ENSRNOG00000032723
drosophila_melanogaster	CG33158	FBGN0053158
caenorhabditis_elegans	K10C3.5	WBGENE00010732

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), GSPT1 (ENSG00000103342), EFTUD2 (ENSG00000108883), HBS1L (ENSG00000112339), EIF2S3 (ENSG00000130741), EEFSEC (ENSG00000132394), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Elongation factor-like GTPase 1 — Q7Z2Z2 (reviewed: Q7Z2Z2)

Alternative names: Elongation factor Tu GTP-binding domain-containing protein 1, Elongation factor-like 1, Protein FAM42A

All UniProt accessions (9): A0A3B3ITU1, A0A8Q3SIF5, A0A8Q3SIM9, A0A8Q3WL51, Q7Z2Z2, H0YK75, H0YKI9, H0YKY7, H0YNW8

UniProt curated annotations — full annotation on UniProt →

Function. GTPase involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with SBDS, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export.

Subunit / interactions. Associates with the 60S ribosomal subunit. Found in a complex consisting of the 60S ribosomal subunit, SBDS and EFL1. Interacts with SBDS and binds to GTP and GDP; the interaction with SBDS decreases EFL1 affinity for GDP and facilitates GDP release.

Tissue specificity. Expressed at low levels in brain. Expression is highly increased in glioma tissues.

Disease relevance. Shwachman-Diamond syndrome 2 (SDS2) [MIM:617941] A form of Shwachman-Diamond syndrome, a disorder characterized by hematopoietic abnormalities, exocrine pancreatic dysfunction, and skeletal dysplasia. Intermittent or chronic neutropenia is the most common hematological manifestation, followed by anemia and thrombocytopenia. Some patients progress to bone marrow failure, myelodysplastic syndrome and malignant transformation, with acute myelogenous leukemia being the most common. Exocrine pancreatic dysfunction is generally the first presenting symptom in infancy. Short stature and metaphyseal dysplasia are the most frequent skeletal manifestations. SDS2 inheritance is autosomal recessive. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. GTPase activity is stimulated in the presence of 60S ribosome subunits.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z2Z2-1	1	yes
Q7Z2Z2-2	2

RefSeq proteins (4): NP_001035700, NP_001309773, NP_001309774, NP_078856* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000640	EFG_V-like	Domain
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR005225	Small_GTP-bd	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035647	EFG_III/V	Homologous_superfamily
IPR041095	EFG_II	Domain
IPR056752	EFL1	Domain

Pfam: PF00009, PF00679, PF14492, PF25118

Enzyme classification (BRENDA):

• EC 3.6.5.3 — protein-synthesizing GTPase (BRENDA: 45 organisms, 101 substrates, 61 inhibitors, 66 Km, 48 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0003–0.27	53
ATP	0.12–0.2	2

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (22 total): sequence variant 5, sequence conflict 3, compositionally biased region 3, binding site 3, mutagenesis site 2, region of interest 2, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5ANB	ELECTRON MICROSCOPY	4.1
5ANC	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z2Z2-F1	74.72	0.17

Functional residue map

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

Ligand- & substrate-binding residues (3): 26–33; 92–96; 146–149

Post-translational modifications (1): 528

Mutagenesis-validated functional residues (2):

Position	Phenotype
33	loss of gtpase activity. abolishes dissociation of eif6 from 60s pre-ribosome subunits.
96	loss of gtpase activity. abolishes dissociation of eif6 from 60s pre-ribosome subunits.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 281 (showing top): GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_RIBOSOME_ASSEMBLY, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_TRANSLATION, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, WTGAAAT_UNKNOWN, TGTGTGA_MIR377, GOBP_ORGANELLE_ASSEMBLY, GOBP_TRANSLATIONAL_ELONGATION, GOBP_GTP_METABOLIC_PROCESS

GO Biological Process (5): cytosolic ribosome assembly (GO:0042256), GTP metabolic process (GO:0046039), translation (GO:0006412), translational elongation (GO:0006414), ribosome biogenesis (GO:0042254)

GO Molecular Function (7): translation elongation factor activity (GO:0003746), GTPase activity (GO:0003924), GTP binding (GO:0005525), ribosome binding (GO:0043022), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): cytosol (GO:0005829), ribonucleoprotein complex (GO:1990904)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational elongation	2
macromolecule biosynthetic process	2
ribosome assembly	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
peptidyltransferase activity	1
translational initiation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
ribonucleoprotein complex biogenesis	1
translation factor activity	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoprotein complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

4525 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFL1	SBDS	Q9Y3A5	978
EFL1	EIF6	P56537	811
EFL1	RPL4	P36578	772
EFL1	DNAJC21	Q5F1R6	722
EFL1	NMD3	Q96D46	690
EFL1	RSL24D1	Q9UHA3	624
EFL1	SRP54	P13624	604
EFL1	LSG1	Q9H089	594
EFL1	MRRF	Q96E11	574
EFL1	MRTO4	Q9UKD2	500
EFL1	GTPBP4	Q9BZE4	489
EFL1	RPA1	P27694	482
EFL1	WDR12	Q9GZL7	475
EFL1	ZNF622	Q969S3	426
EFL1	CLMN	Q96JQ2	426

IntAct

34 interactions, top by confidence:

A	B	Type	Score
SBDS	EFL1	psi-mi:“MI:0407”(direct interaction)	0.710
EFL1	SBDS	psi-mi:“MI:0407”(direct interaction)	0.710
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
TRIP6	WTIP	psi-mi:“MI:0914”(association)	0.530
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
EFTUD2	AQR	psi-mi:“MI:0914”(association)	0.530
EFL1	H1-4	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
Nedd1		psi-mi:“MI:0914”(association)	0.350
Haus1	LTF	psi-mi:“MI:0914”(association)	0.350
Rbm8a	GOSR1	psi-mi:“MI:0914”(association)	0.350
Myl12b	MYL6	psi-mi:“MI:0914”(association)	0.350
Sptlc2	SURF4	psi-mi:“MI:0914”(association)	0.350
TUBGCP4	PZP	psi-mi:“MI:0914”(association)	0.350
Chmp4b	BDP1	psi-mi:“MI:0914”(association)	0.350
Espl1	BDP1	psi-mi:“MI:0914”(association)	0.350
SASS6	NFIB	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
VCP	SHTN1	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DND1	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
CDC14A	CEP290	psi-mi:“MI:2364”(proximity)	0.270
RBM15	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
SBDS	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (86): EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), ABCF2 (Co-fractionation), DDX51 (Co-fractionation), EFTUD1 (Co-fractionation), EFTUD1 (Co-fractionation), EFTUD1 (Co-fractionation), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS), EFTUD1 (Affinity Capture-MS)

ESM2 similar proteins: A2ARP1, A2RRU1, A7MB78, A7Z050, F4J8C6, O00562, O08739, O09178, O14976, O35954, O43314, O74429, P0C644, P10759, P13807, P13834, P32019, P41229, P41230, P54310, P91309, P97874, Q01432, Q01433, Q02356, Q30DN6, Q38JA7, Q3V1D3, Q5R9H0, Q5RDF1, Q5REW0, Q5U2N3, Q5XHF8, Q5XUN4, Q6IQX0, Q6PFW1, Q6ZQB6, Q7Z2Z2, Q7Z3E5, Q80Y84

Diamond homologs: A0B7D5, A0RW30, A0SXL6, A1RVX2, A3CXM8, A3DMV6, A3MSN3, A4FUD3, A4WMR8, A4YCV9, A5DI11, A5ULM6, A7I4X4, A8ACA7, B0R8C8, B1L7Q0, B1YE08, B6YVG5, B8D6B2, B8GJK8, C3MQ53, C3MVH1, C3N5S0, C3NED6, C3NHB6, C4KHE9, C4YJQ8, C5A6N7, C6A4M0, C7NYH7, D3E3N9, F4JWP9, O08810, O14460, O23755, O27131, O28385, O59521, O74945, O93632

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EFL1	up-regulates	EIF6
SBDS	up-regulates	EFL1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	281
Likely benign	247
Benign	17

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1686816	NM_024580.6(EFL1):c.2647T>G (p.Cys883Gly)	Pathogenic
1686818	NM_024580.6(EFL1):c.2478dup (p.Gly827fs)	Pathogenic
1686814	NM_024580.6(EFL1):c.2260C>T (p.Arg754Ter)	Likely pathogenic
1686815	NM_024580.6(EFL1):c.1514T>C (p.Phe505Ser)	Likely pathogenic
1686819	NM_024580.6(EFL1):c.89A>G (p.His30Arg)	Likely pathogenic
4819861	NM_024580.6(EFL1):c.1612-2A>G	Likely pathogenic

SpliceAI

4075 predictions. Top by Δscore:

Variant	Effect	Δscore
15:82130563:T:C	acceptor_gain	1.0000
15:82130563:T:TC	acceptor_gain	1.0000
15:82130565:G:C	acceptor_gain	1.0000
15:82130565:G:GC	acceptor_gain	1.0000
15:82138708:T:TA	donor_gain	1.0000
15:82157711:A:C	donor_gain	1.0000
15:82163848:CTTAC:C	donor_loss	1.0000
15:82163849:TTACT:T	donor_loss	1.0000
15:82163850:TACTT:T	donor_loss	1.0000
15:82163851:A:AC	donor_gain	1.0000
15:82163851:A:T	donor_loss	1.0000
15:82163852:C:CC	donor_gain	1.0000
15:82163852:CT:C	donor_gain	1.0000
15:82163852:CTTGG:C	donor_gain	1.0000
15:82163980:TATTC:T	acceptor_gain	1.0000
15:82163982:TTC:T	acceptor_gain	1.0000
15:82163983:TC:T	acceptor_gain	1.0000
15:82163984:CC:C	acceptor_gain	1.0000
15:82163985:C:CC	acceptor_gain	1.0000
15:82163985:C:CG	acceptor_loss	1.0000
15:82219646:TCTTA:T	donor_loss	1.0000
15:82219647:CTTAC:C	donor_loss	1.0000
15:82219648:TTACC:T	donor_loss	1.0000
15:82219649:TACCC:T	donor_loss	1.0000
15:82219650:AC:A	donor_gain	1.0000
15:82219651:CC:C	donor_gain	1.0000
15:82219651:CCCTT:C	donor_gain	1.0000
15:82219706:T:A	donor_gain	1.0000
15:82219816:CAC:C	acceptor_gain	1.0000
15:82219819:C:CC	acceptor_gain	1.0000

AlphaMissense

7410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:82241351:A:C	F99L	1.000
15:82241351:A:T	F99L	1.000
15:82241353:A:G	F99L	1.000
15:82252771:C:A	R55M	1.000
15:82130394:C:A	R1114S	0.999
15:82130394:C:G	R1114S	0.999
15:82130452:C:G	R1095P	0.999
15:82138689:G:T	A1048D	0.999
15:82138733:G:C	S1033R	0.999
15:82138733:G:T	S1033R	0.999
15:82138735:T:G	S1033R	0.999
15:82138756:C:G	A1026P	0.999
15:82157737:C:G	R669P	0.999
15:82157743:A:G	L667P	0.999
15:82157770:A:T	V658D	0.999
15:82157816:C:G	A643P	0.999
15:82157824:A:G	L640S	0.999
15:82157845:A:G	L633P	0.999
15:82163876:A:T	V620D	0.999
15:82228218:A:G	W348R	0.999
15:82228218:A:T	W348R	0.999
15:82238317:A:G	W241R	0.999
15:82238317:A:T	W241R	0.999
15:82238330:A:C	S236R	0.999
15:82238330:A:T	S236R	0.999
15:82238332:T:G	S236R	0.999
15:82240485:C:G	R150P	0.999
15:82241352:A:G	F99S	0.999
15:82241356:C:G	D98H	0.999
15:82241360:G:C	H96Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000021396 (15:82212348 T>C), RS1000022419 (15:82136766 A>T), RS1000027458 (15:82185358 TTAAATAAAA>T), RS1000072581 (15:82218777 T>A), RS1000128691 (15:82182361 T>C), RS1000136910 (15:82176489 C>CA), RS1000169636 (15:82133542 T>C), RS1000179614 (15:82233381 C>A), RS1000225332 (15:82149516 A>C), RS1000278069 (15:82182779 C>T), RS1000283065 (15:82188143 G>A), RS1000304305 (15:82140062 C>T), RS1000324565 (15:82231084 C>A,T), RS1000390380 (15:82158003 A>C), RS1000405857 (15:82150992 A>C,G)

Disease associations

OMIM: gene MIM:617538 | disease phenotypes: MIM:617941, MIM:260400, MIM:300755

GenCC curated gene-disease

Disease	Classification	Inheritance
Shwachman-Diamond syndrome 2	Strong	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
Shwachman-Diamond syndrome 2	Definitive	AR

Mondo (4): Shwachman-Diamond syndrome 2 (MONDO:0044205), Shwachman-Diamond syndrome (MONDO:0009833), primary ovarian failure (MONDO:0005387), immunodeficiency disease (MONDO:0021094)

Orphanet (2): Shwachman-Diamond syndrome (Orphanet:811), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000155	Oral ulcer
HP:0000218	High palate
HP:0000246	Sinusitis
HP:0000252	Microcephaly
HP:0000356	Abnormality of the outer ear
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000819	Diabetes mellitus
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000886	Deformed rib cage
HP:0000907	Anterior rib cupping
HP:0000924	Abnormality of the skeletal system
HP:0000938	Osteopenia
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001167	Abnormal finger morphology
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001367	Abnormal joint morphology
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001601	Laryngomalacia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST003069_2	Left superior temporal gyrus thickness (schizophrenia interaction)	9.000000e-07
GCST003901_10	Cognitive decline (age-related)	2.000000e-06
GCST005141_24	Cognitive ability (MTAG)	1.000000e-10
GCST005142_38	Cognitive ability	3.000000e-06
GCST005142_39	Cognitive ability	2.000000e-08
GCST005316_499	Intelligence (MTAG)	1.000000e-08
GCST005316_500	Intelligence (MTAG)	2.000000e-10
GCST005316_501	Intelligence (MTAG)	4.000000e-10
GCST005316_502	Intelligence (MTAG)	1.000000e-10
GCST006269_919	General cognitive ability	2.000000e-08
GCST007277_21	Tourette syndrome	7.000000e-06
GCST009391_1001	Metabolite levels	5.000000e-06
GCST010002_102	Refractive error	3.000000e-27
GCST012214_3	Alzheimer’s disease	6.000000e-06
GCST90020028_1757	Hip circumference adjusted for BMI	4.000000e-08
GCST90020028_1758	Hip circumference adjusted for BMI	7.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0010358	lysophosphatidylcholine 16:1 measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression, increases expression	3
Calcitriol	increases expression, affects cotreatment	3
Cyclosporine	increases expression	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arbutin	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Dactinomycin	affects cotreatment, increases secretion	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)