GET1

Summary

GET1 (guided entry of tail-anchored proteins factor 1, HGNC:12790) is a protein-coding gene on chromosome 21q22.2, encoding Guided entry of tail-anchored proteins factor 1 (O00258). Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER). It is a selective cancer dependency (DepMap: 46.6% of cell lines).

This gene is located in the candidate region for congenital heart disease (CHD) in Down syndrome (DS). It encodes a basic protein that functions as a receptor that promotes insertion of tail-anchored proteins in the endoplasmic reticulum membrane. This gene is located at a maternally-methylated differentially methylated region (DMR); however, its transcription may be biallelic, not imprinted. Alternative splicing results in different transcript variants. A pseudogene has been defined on chromosome 4.

Source: NCBI Gene 7485 — RefSeq curated summary.

At a glance

• Gene–disease (curated): parenti-mignot neurodevelopmental syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 688 total — 10 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 26
• Cancer dependency (DepMap): dependent in 46.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004627

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12790
Approved symbol	GET1
Name	guided entry of tail-anchored proteins factor 1
Location	21q22.2
Locus type	gene with protein product
Status	Approved
Aliases	CHD5
Ensembl gene	ENSG00000182093
Ensembl biotype	protein_coding
OMIM	602915
Entrez	7485

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 9 protein_coding, 7 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000380708, ENST00000380713, ENST00000398753, ENST00000415847, ENST00000442773, ENST00000466787, ENST00000471468, ENST00000476914, ENST00000478273, ENST00000480690, ENST00000487869, ENST00000490860, ENST00000623703, ENST00000647678, ENST00000647911, ENST00000648495, ENST00000649100, ENST00000649170, ENST00000649224, ENST00000649499, ENST00000649822, ENST00000650208, ENST00000650376

RefSeq mRNA: 6 — MANE Select: NM_004627 NM_001146218, NM_001350293, NM_001350294, NM_001350295, NM_001350296, NM_004627

CCDS: CCDS13664, CCDS54485

Canonical transcript exons

ENST00000649170 — 5 exons

Exon	Start	End
ENSE00001486004	39396866	39397889
ENSE00003651735	39391769	39391836
ENSE00003757548	39390698	39390863
ENSE00003788222	39393166	39393280
ENSE00003834584	39380326	39380486

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.1053 / max 177.2784, expressed in 1786 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189159	23.2138	1796
189164	5.1496	1449
189163	4.8015	1365
189161	2.8863	1353
189160	1.8880	1088
189162	0.3799	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	98.76	gold quality
substantia nigra pars compacta	UBERON:0001965	98.11	gold quality
epithelium of bronchus	UBERON:0002031	98.09	gold quality
pons	UBERON:0000988	98.07	gold quality
adult organism	UBERON:0007023	97.97	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.96	gold quality
choroid plexus epithelium	UBERON:0003911	97.90	gold quality
superior vestibular nucleus	UBERON:0007227	97.83	gold quality
bronchus	UBERON:0002185	97.78	gold quality
cortical plate	UBERON:0005343	97.77	gold quality
hypothalamus	UBERON:0001898	97.69	gold quality
subthalamic nucleus	UBERON:0001906	97.56	gold quality
lateral globus pallidus	UBERON:0002476	97.55	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.54	gold quality
spinal cord	UBERON:0002240	97.43	gold quality
pigmented layer of retina	UBERON:0001782	97.28	gold quality
medulla oblongata	UBERON:0001896	97.13	gold quality
ventricular zone	UBERON:0003053	97.10	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.09	gold quality
amygdala	UBERON:0001876	97.02	gold quality
ganglionic eminence	UBERON:0004023	96.86	gold quality
substantia nigra	UBERON:0002038	96.85	gold quality
nucleus accumbens	UBERON:0001882	96.83	gold quality
orbitofrontal cortex	UBERON:0004167	96.80	gold quality
midbrain	UBERON:0001891	96.71	gold quality
Ammon’s horn	UBERON:0001954	96.63	gold quality
caudate nucleus	UBERON:0001873	96.60	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.47	gold quality
prefrontal cortex	UBERON:0000451	96.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	no	2017.75
E-MTAB-6379	no	340.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting GET1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 46.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• The coiled-coil domain of WRB is the binding site for TRC40/Asna1. (PMID:21444755)
• Results indicate calcium-modulating cyclophilin ligand (CAML) and WRB as components of the TRC40 receptor complex and a crucial mechanism for driving ER membrane insertion of TA proteins in mammalian cells. (PMID:23041287)
• WRB gene contains a maternally imprinted differentially methylated region (DMR). The maternally inherited 5mCpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in twelve biosamples (brain, blood, fallopian tube, fetal large and small intestine, hESCs, large airway epithelial cells, thyroid, muscle, epidermal keratinocytes, ovary, skin, and testis). (PMID:27100087)
• A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 x 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (PMID:30098192)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps3	ENSDARG00000103007
mus_musculus	Get1	ENSMUSG00000023147
drosophila_melanogaster	RpS3	FBGN0002622
caenorhabditis_elegans		WBGENE00004472

Paralogs (1): RPS3 (ENSG00000149273)

Protein

Protein identifiers

Guided entry of tail-anchored proteins factor 1 — O00258 (reviewed: O00258)

Alternative names: Congenital heart disease 5 protein, Tail-anchored protein insertion receptor WRB, Tryptophan-rich basic protein

All UniProt accessions (12): O00258, A0A096LNK8, A0A096LNT6, A0A3B3ISA8, A0A3B3ISE5, A0A3B3IT79, A0A3B3IUG4, B4DLW3, B7Z1T1, C9JLV3, H7BYE5, H7C384

UniProt curated annotations — full annotation on UniProt →

Function. Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER). Together with CAMLG/GET2, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. Required to ensure correct topology and ER insertion of CAMLG.

Subunit / interactions. Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40. Within the complex, GET1 and CAMLG form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer. Interacts with CAMLG (via C-terminus). GET3 shows a higher affinity for CAMLG than for GET1.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the WRB/GET1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00258-1	1	yes
O00258-2	2

RefSeq proteins (6): NP_001139690, NP_001337222, NP_001337223, NP_001337224, NP_001337225, NP_004618* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028945	Get1	Family
IPR029012	Helix_hairpin_bin_sf	Homologous_superfamily

Pfam: PF04420

UniProt features (21 total): helix 7, topological domain 4, transmembrane region 3, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, strand 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8CQZ	X-RAY DIFFRACTION	2.8
8CR1	ELECTRON MICROSCOPY	3.2
6SO5	ELECTRON MICROSCOPY	4.2
8CR2	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00258-F1	78.15	0.23

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane

MSigDB gene sets: 396 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_OTIC_VESICLE_DEVELOPMENT, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, GOBP_NEUROGENESIS, GOBP_MALE_GAMETE_GENERATION

GO Biological Process (9): post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620), sensory perception of sound (GO:0007605), protein insertion into ER membrane (GO:0045048), synapse organization (GO:0050808), protein stabilization (GO:0050821), establishment of localization in cell (GO:0051649), otic vesicle development (GO:0071599), tail-anchored membrane protein insertion into ER membrane (GO:0071816), establishment of protein localization to membrane (GO:0090150)

GO Molecular Function (2): protein-membrane adaptor activity (GO:0043495), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), GET complex (GO:0043529), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
protein targeting to membrane	1
protein targeting to ER	1
sensory perception of mechanical stimulus	1
endoplasmic reticulum organization	1
protein localization to organelle	1
protein insertion into membrane	1
cell junction organization	1
regulation of protein stability	1
establishment of localization	1
cellular localization	1
sensory organ development	1
tube development	1
inner ear development	1
epithelium development	1
protein insertion into ER membrane	1
establishment of protein localization	1
localization within membrane	1
protein-macromolecule adaptor activity	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum protein-containing complex	1
cytoplasm	1
endomembrane system	1
cellular anatomical structure	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GET1	CAMLG	P49069	994
GET1	GET3	O43681	984
GET1	GET4	Q7L5D6	914
GET1	UBL4A	P11441	814
GET1	HMGN1	P05114	802
GET1	EMC3	Q9P0I2	795
GET1	SGTA	O43765	780
GET1	OXA1L	Q15070	767
GET1	SEC61A1	P38378	700
GET1	GYPA	P02724	678
GET1	EMC6	Q9BV81	623
GET1	TMCO1	Q9UM00	581
GET1	TMEM208	Q9BTX3	572
GET1	PSMG1	O95456	531
GET1	SERP1	Q9Y6X1	528

IntAct

121 interactions, top by confidence:

A	B	Type	Score
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
GET3	GET1	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SLC19A3	GET1	psi-mi:“MI:0915”(physical association)	0.560
CAMLG	GET1	psi-mi:“MI:0915”(physical association)	0.560
COMT	GET1	psi-mi:“MI:0915”(physical association)	0.560
COX20	GET1	psi-mi:“MI:0915”(physical association)	0.560
ERG28	GET1	psi-mi:“MI:0915”(physical association)	0.560
GET1	SLC19A3	psi-mi:“MI:0915”(physical association)	0.560
GET1	APOL2	psi-mi:“MI:0915”(physical association)	0.560
GET1	ABHD5	psi-mi:“MI:0915”(physical association)	0.560
GET1	TECR	psi-mi:“MI:0915”(physical association)	0.560
GET1	HMOX2	psi-mi:“MI:0915”(physical association)	0.560
GET1	TM4SF19	psi-mi:“MI:0915”(physical association)	0.560
GET1	CAMLG	psi-mi:“MI:0915”(physical association)	0.560
GET1	CCL4L1	psi-mi:“MI:0915”(physical association)	0.560
GET1	PLPP4	psi-mi:“MI:0915”(physical association)	0.560
GET1	AQP1	psi-mi:“MI:0915”(physical association)	0.560
GET1	SLC35E3	psi-mi:“MI:0915”(physical association)	0.560
GET1	TMEM42	psi-mi:“MI:0915”(physical association)	0.560
GET1	TFRC	psi-mi:“MI:0915”(physical association)	0.560
GET1	CLCN7	psi-mi:“MI:0915”(physical association)	0.560
GET1	COX20	psi-mi:“MI:0915”(physical association)	0.560
GET1	ERG28	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (81): WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS), WRB (Affinity Capture-MS)

ESM2 similar proteins: A2RV80, A4FUD4, A4FV75, A5A6S6, A6ZIQ8, B2ZXD5, B5X1G3, B7ZAQ6, O00258, O00623, O75031, P0CG08, P60570, Q1H5D2, Q3SZ26, Q3SZM3, Q3TMP8, Q3TYS2, Q3UBZ5, Q4R7G8, Q5BIM9, Q5EAQ1, Q5F448, Q5R6K7, Q5RBY5, Q5REE3, Q5ZKG8, Q6AXN4, Q6AXU7, Q6AYA6, Q6DDW6, Q6DRM0, Q6P6S5, Q801N6, Q8BS95, Q8K0D7, Q8L7N4, Q8TCT6, Q8VCB1, Q8VCM5

Diamond homologs: O00258, Q3SZ26, Q5R6K7, Q6DRM0, Q6P6S5, Q8K0D7, B0D1L7, A1CXY5, B0Y5H9, B6HS10, B8NA66, Q2UG70, Q4WNN2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GET1	“form complex”	“GET complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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
SLC-mediated transmembrane transport	6	8.7×	5e-03
Transport of small molecules	11	6.8×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	28
Uncertain significance	536
Likely benign	53
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2022088	NM_015557.3(CHD5):c.3684del (p.Asn1229fs)	Pathogenic
2104557	NM_015557.3(CHD5):c.5830C>T (p.Gln1944Ter)	Pathogenic
2181026	NM_015557.3(CHD5):c.1370_1371insAG (p.Cys457Ter)	Pathogenic
3376973	NM_015557.3(CHD5):c.1721del (p.Leu574fs)	Pathogenic
3901205	NM_015557.3(CHD5):c.3056del (p.Leu1019fs)	Pathogenic
4075496	NM_015557.3(CHD5):c.4180C>T (p.Arg1394Ter)	Pathogenic
4536260	NM_015557.3(CHD5):c.2129G>A (p.Trp710Ter)	Pathogenic
4813050	NM_015557.3(CHD5):c.457G>T (p.Glu153Ter)	Pathogenic
57360	GRCh38/hg38 21q22.13-22.3(chr21:37135738-42434515)x1	Pathogenic
58041	GRCh38/hg38 1p36.32-36.31(chr1:4799319-6129675)x3	Pathogenic
1213025	NM_015557.3(CHD5):c.2792G>A (p.Arg931Gln)	Likely pathogenic
1321987	NM_015557.3(CHD5):c.4171+5G>A	Likely pathogenic
2444409	NM_015557.3(CHD5):c.4572C>A (p.Tyr1524Ter)	Likely pathogenic
2497742	NM_015557.3(CHD5):c.1490_1496del (p.Leu497fs)	Likely pathogenic
2663914	NM_015557.3(CHD5):c.2795T>G (p.Leu932Arg)	Likely pathogenic
2691722	NM_015557.3(CHD5):c.3988C>T (p.Gln1330Ter)	Likely pathogenic
3024552	NM_015557.3(CHD5):c.3187G>A (p.Glu1063Lys)	Likely pathogenic
3251189	NM_015557.3(CHD5):c.1590+1G>T	Likely pathogenic
3251946	NM_015557.3(CHD5):c.5596_5597delinsTT (p.Glu1866Leu)	Likely pathogenic
3375462	NM_015557.3(CHD5):c.139C>T (p.Leu47Phe)	Likely pathogenic
3376984	NM_015557.3(CHD5):c.3305C>A (p.Ala1102Glu)	Likely pathogenic
3382657	NM_015557.3(CHD5):c.2552G>A (p.Arg851His)	Likely pathogenic
3767292	NM_015557.3(CHD5):c.5556del (p.Ala1853fs)	Likely pathogenic
3832812	NM_015557.3(CHD5):c.3370C>T (p.Pro1124Ser)	Likely pathogenic
4813049	NM_015557.3(CHD5):c.840dup (p.Ile281fs)	Likely pathogenic
4813468	NM_015557.3(CHD5):c.3366G>C (p.Trp1122Cys)	Likely pathogenic
4819624	NM_015557.3(CHD5):c.3397C>T (p.Arg1133Cys)	Likely pathogenic
4820088	NM_015557.3(CHD5):c.2514del (p.Ile839fs)	Likely pathogenic
995776	NM_015557.3(CHD5):c.612dup (p.Ser205fs)	Likely pathogenic
995778	NM_015557.3(CHD5):c.1279G>A (p.Glu427Lys)	Likely pathogenic

SpliceAI

9126 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6106610:CCTGA:C	donor_loss	1.0000
1:6106611:CTGA:C	donor_loss	1.0000
1:6106612:TGAC:T	donor_loss	1.0000
1:6106613:GAC:G	donor_loss	1.0000
1:6106615:C:G	donor_loss	1.0000
1:6106615:CCTG:C	donor_gain	1.0000
1:6106775:CAGGA:C	acceptor_gain	1.0000
1:6106776:AGGA:A	acceptor_gain	1.0000
1:6106777:GGA:G	acceptor_gain	1.0000
1:6106778:GA:G	acceptor_gain	1.0000
1:6106780:C:CC	acceptor_gain	1.0000
1:6106782:G:C	acceptor_gain	1.0000
1:6106793:C:CT	acceptor_gain	1.0000
1:6109793:A:AC	donor_gain	1.0000
1:6109793:AC:A	donor_gain	1.0000
1:6109794:C:CA	donor_gain	1.0000
1:6109794:C:CC	donor_gain	1.0000
1:6110391:GA:G	donor_loss	1.0000
1:6110392:ACCT:A	donor_loss	1.0000
1:6110393:C:CT	donor_loss	1.0000
1:6110542:T:TC	acceptor_gain	1.0000
1:6111776:T:TA	donor_gain	1.0000
1:6111882:CT:C	acceptor_gain	1.0000
1:6111884:C:CA	acceptor_loss	1.0000
1:6111884:C:CC	acceptor_gain	1.0000
1:6112154:T:TA	donor_gain	1.0000
1:6112173:A:C	donor_gain	1.0000
1:6112182:T:TA	donor_gain	1.0000
1:6112188:T:TA	donor_gain	1.0000
1:6112196:T:TA	donor_gain	1.0000

AlphaMissense

1140 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:39390800:T:C	F69L	1.000
21:39390801:T:G	F69C	1.000
21:39390802:T:A	F69L	1.000
21:39390802:T:G	F69L	1.000
21:39390813:C:A	A73D	1.000
21:39390825:G:C	R77T	1.000
21:39390826:A:C	R77S	1.000
21:39390826:A:T	R77S	1.000
21:39390801:T:C	F69S	0.999
21:39390804:C:A	A70D	0.999
21:39390819:T:C	L75P	0.999
21:39390825:G:T	R77I	0.999
21:39390852:T:C	L86P	0.999
21:39396874:G:A	G154R	0.999
21:39396874:G:C	G154R	0.999
21:39396886:T:A	W158R	0.999
21:39396886:T:C	W158R	0.999
21:39390800:T:A	F69I	0.998
21:39390800:T:G	F69V	0.998
21:39390817:G:C	R74S	0.998
21:39390817:G:T	R74S	0.998
21:39396875:G:A	G154E	0.998
21:39396875:G:T	G154V	0.998
21:39396883:T:C	C157R	0.998
21:39396898:T:C	C162R	0.998
21:39390812:G:C	A73P	0.997
21:39390816:G:C	R74T	0.997
21:39390824:A:G	R77G	0.996
21:39391778:G:C	R93P	0.996
21:39393232:T:A	W135R	0.996

dbSNP variants (sampled 300 via entrez): RS1000020061 (21:39398267 G>A), RS1000031958 (21:39386248 A>C), RS1000086481 (21:39380748 C>A), RS1000184438 (21:39389720 C>T), RS1000186755 (21:39406547 C>G,T), RS1000377015 (21:39409685 T>G), RS1000411696 (21:39381682 T>C,G), RS1000438592 (21:39418699 C>T), RS1000516915 (21:39416451 G>A), RS1000544416 (21:39391162 T>C), RS1000563144 (21:39408495 T>C), RS1000611342 (21:39421368 G>A,T), RS1000622679 (21:39421178 C>T), RS1000721147 (21:39414734 CTCTCTCTCTG>C), RS1000786001 (21:39413496 G>A)

Disease associations

OMIM: gene MIM:602915 | disease phenotypes: MIM:619873, MIM:610805, MIM:617183

GenCC curated gene-disease

Disease	Classification	Inheritance
parenti-mignot neurodevelopmental syndrome	Strong	Autosomal dominant
schizophrenia	Limited	Unknown

Mondo (7): parenti-mignot neurodevelopmental syndrome (MONDO:0859249), congenital heart disease (MONDO:0005453), congenital anomaly of kidney and urinary tract (MONDO:0019719), neurodevelopmental disorder (MONDO:0700092), Harel-Yoon syndrome (MONDO:0014958), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090)

Orphanet (3): Renal or urinary tract malformation (Orphanet:93545), Ocular anomalies-axonal neuropathy-developmental delay syndrome (Orphanet:496790), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000286	Epicanthus
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000426	Prominent nasal bridge
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001363	Craniosynostosis
HP:0002007	Frontal bossing
HP:0003593	Infantile onset
HP:0005274	Prominent nasal tip
HP:0007018	Attention deficit hyperactivity disorder
HP:0008551	Microtia
HP:0012166	Skin-picking
HP:0100716	Self-injurious behavior

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002934_15	Zinc levels	6.000000e-06
GCST004607_189	Plateletcrit	1.000000e-11
GCST008741_3	Non-accommodative esotropia	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
Decitabine	affects expression, increases expression	2
Air Pollutants	affects methylation, increases abundance, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	affects methylation, increases abundance, decreases expression	2
dicrotophos	decreases expression	1
bisphenol A	affects cotreatment, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
azoxystrobin	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
Temozolomide	decreases expression	1
Lycopene	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Quercetin	decreases expression	1
Rotenone	increases expression	1
Thiram	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety