BRAT1

Summary

BRAT1 (BRCA1 associated ATM activator 1, HGNC:21701) is a protein-coding gene on chromosome 7p22.3, encoding Integrator complex assembly factor BRAT1 (Q6PJG6). Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex. It is a selective cancer dependency (DepMap: 43.5% of cell lines).

The protein encoded by this ubiquitously expressed gene interacts with the tumor suppressing BRCA1 (breast cancer 1) protein and and the ATM (ataxia telangiectasia mutated) protein. ATM is thought to be a master controller of cell cycle checkpoint signalling pathways that are required for cellular responses to DNA damage such as double-strand breaks that are induced by ionizing radiation and complexes with BRCA1 in the multi-protein complex BASC (BRAC1-associated genome surveillance complex). The protein encoded by this gene is thought to play a role in the DNA damage pathway regulated by BRCA1 and ATM.

Source: NCBI Gene 221927 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neonatal-onset encephalopathy with rigidity and seizures (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,389 total — 76 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 61
• Cancer dependency (DepMap): dependent in 43.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_152743

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21701
Approved symbol	BRAT1
Name	BRCA1 associated ATM activator 1
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC22916
Ensembl gene	ENSG00000106009
Ensembl biotype	protein_coding
OMIM	614506
Entrez	221927

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 44 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000340611, ENST00000421712, ENST00000467558, ENST00000469750, ENST00000473879, ENST00000493232, ENST00000890462, ENST00000890463, ENST00000890464, ENST00000890465, ENST00000890466, ENST00000890467, ENST00000890468, ENST00000890469, ENST00000890470, ENST00000890471, ENST00000890472, ENST00000890473, ENST00000890474, ENST00000890475, ENST00000890476, ENST00000890477, ENST00000890478, ENST00000890479, ENST00000890480, ENST00000890481, ENST00000890482, ENST00000890483, ENST00000890484, ENST00000917319, ENST00000917320, ENST00000917321, ENST00000917322, ENST00000917323, ENST00000917324, ENST00000917325, ENST00000917326, ENST00000917327, ENST00000917328, ENST00000917329, ENST00000917330, ENST00000970712, ENST00000970713, ENST00000970714, ENST00000970715, ENST00000970716, ENST00000970717, ENST00000970718, ENST00000970719

RefSeq mRNA: 3 — MANE Select: NM_152743 NM_001350626, NM_001350627, NM_152743

CCDS: CCDS5334

Canonical transcript exons

ENST00000340611 — 14 exons

Exon	Start	End
ENSE00000976228	2540979	2541052
ENSE00001687632	2537810	2538764
ENSE00001848191	2555487	2555524
ENSE00003493759	2542120	2542211
ENSE00003589382	2554305	2554447
ENSE00003604869	2539179	2539351
ENSE00003612441	2544909	2545056
ENSE00003635847	2539544	2539642
ENSE00003640341	2541298	2541484
ENSE00003666106	2539786	2539888
ENSE00003690059	2541718	2541836
ENSE00003693120	2543590	2543962
ENSE00003705394	2547324	2547478
ENSE00003710814	2543204	2543323

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 91.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9575 / max 90.7645, expressed in 1753 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82494	5.1324	1676
82493	1.0418	644
82495	0.9884	610
82496	0.7949	461

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	91.84	gold quality
granulocyte	CL:0000094	91.75	gold quality
right adrenal gland	UBERON:0001233	91.74	gold quality
left adrenal gland	UBERON:0001234	91.69	gold quality
right adrenal gland cortex	UBERON:0035827	91.64	gold quality
right testis	UBERON:0004534	90.96	gold quality
left testis	UBERON:0004533	90.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.51	gold quality
right uterine tube	UBERON:0001302	90.29	gold quality
right ovary	UBERON:0002118	90.26	gold quality
cerebellar hemisphere	UBERON:0002245	90.05	gold quality
apex of heart	UBERON:0002098	89.98	gold quality
adrenal cortex	UBERON:0001235	89.84	gold quality
cerebellar cortex	UBERON:0002129	89.75	gold quality
endocervix	UBERON:0000458	89.58	gold quality
left ovary	UBERON:0002119	89.42	gold quality
adenohypophysis	UBERON:0002196	89.40	gold quality
mucosa of transverse colon	UBERON:0004991	89.40	gold quality
skin of leg	UBERON:0001511	89.13	gold quality
body of stomach	UBERON:0001161	89.04	gold quality
adrenal gland	UBERON:0002369	89.03	gold quality
left uterine tube	UBERON:0001303	88.94	gold quality
body of uterus	UBERON:0009853	88.87	gold quality
right lobe of thyroid gland	UBERON:0001119	88.83	gold quality
ectocervix	UBERON:0012249	88.82	gold quality
skin of abdomen	UBERON:0001416	88.47	gold quality
ventricular zone	UBERON:0003053	88.47	gold quality
left lobe of thyroid gland	UBERON:0001120	87.97	gold quality
mucosa of stomach	UBERON:0001199	87.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting BRAT1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-134-3P	96.83	66.22	1001
HSA-MIR-4764-3P	96.81	67.94	580
HSA-MIR-4433A-5P	96.79	65.01	599
HSA-MIR-3657	96.33	66.29	608
HSA-MIR-4330	95.44	66.39	993

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 43.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 22)

• Study identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. (PMID:22279524)
• Data on crystal structure of BRCA1 binding with phosphopeptides suggest that C-terminal domain of BRCA1 interacts with BAAT1 and ATRIP with preferences for specific side chains; in BAAT1, phospho-Ser269 and Phe272 are the main interacting residues. (PMID:24073851)
• Findings suggest novel roles of BRAT1 in cell proliferation and mitochondrial functions. (PMID:25070371)
• Our results further support that mutations of BRAT1 could lead to epileptic encephalopathy. (PMID:25319849)
• Ndfip1 is required during stress for ubiquitinating and trafficking BRAT1 into the nucleus. (PMID:25631046)
• We conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy. (PMID:26535877)
• compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. (PMID:27282546)
• our data expand the clinical symptoms and demonstrate variability in the natural clinical course of BRAT1-associated phenotypes. Patients with early onset seizures, postnatal microcephaly, feeding problems, and muscular hypertonia or contractures should hence be screened for BRAT1 mutations. (PMID:27282648)
• we report two affected siblings with compound heterozygous truncating mutations in BRAT1 and intra-familial phenotypic heterogeneity, with a less severe disease course in the female sibling. This phenotypic variability should be taken into account when treating patients with BRAT1-associated neurodegenerative disease. (PMID:27480663)
• Biallelic sequence variants in BRAT1 have been reported to cause a variety of ocular and systemic manifestations, but to our knowledge, this is the first report of inner retinal dysfunction manifest as selective loss of full-field ERG scotopic and photopic b-wave amplitudes. (PMID:28635423)
• Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells derived from familial Alzheimer’s disease (FAD) patients, studied role of BRCA1 protein underlying molecular neurodegeneration. Whole-transcriptome approach showed disturbances in cell cycle and DNA damage response in FAD fibroblasts; increased BRCA1 Ser1524 phosphorylated and abnormal PSEN1 ubiquitination and subcellular distribution. (PMID:29439343)
• A first reported case of Chinese origin was identified with a BRAT1 mutation linked to lethal neonatal rigidity and multifocal seizure syndrome. (PMID:30346566)
• The neuropathology is extensively discussed and hypotheses put forward that may shed light on etiology of brain symptomatology within the context of BRAT1 mutations (PMID:30786674)
• BRAT1 encephalopathy: a recessive cause of epilepsy of infancy with migrating focal seizures. (PMID:31868227)
• A novel pathogenic variant of BRAT1 gene causes rigidity and multifocal seizure syndrome, lethal neonatal. (PMID:32345087)
• Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome. (PMID:33790413)
• Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance. (PMID:34747546)
• BRAT1 links Integrator and defective RNA processing with neurodegeneration. (PMID:36028512)
• Compound heterozygous loss-of-function variants in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome. (PMID:36367347)
• Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy. (PMID:36599696)
• BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients. (PMID:37344571)
• Neuronal differentiation requires BRAT1 complex to remove REST from chromatin. (PMID:38805275)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	brat1	ENSDARG00000062585
mus_musculus	Brat1	ENSMUSG00000000148
rattus_norvegicus	Brat1	ENSRNOG00000001236
drosophila_melanogaster	CG7044	FBGN0038854

Protein

Protein identifiers

Integrator complex assembly factor BRAT1 — Q6PJG6 (reviewed: Q6PJG6)

Alternative names: BRCA1-associated ATM activator 1, BRCA1-associated protein required for ATM activation protein 1

All UniProt accessions (2): Q6PJG6, F8WDN5

UniProt curated annotations — full annotation on UniProt →

Function. Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex. Associates with INTS9 and INTS11 in the cytoplasm and blocks the active site of INTS11 to inhibit the endonuclease activity of INTS11 before formation of the full integrator complex. Following dissociation of WDR73 of the complex, BRAT1 facilitates the nuclear import of the INTS9-INTS11 heterodimer. In the nucleus, INTS4 is integrated to the INTS9-INTS11 heterodimer and BRAT1 is released from the mature RNA endonuclease module by inositol hexakisphosphate (InsP6). BRAT1 is also involved in DNA damage response; activates kinases ATM, SMC1A and PRKDC by modulating their phosphorylation status following ionizing radiation (IR) stress. Plays a role in regulating mitochondrial function and cell proliferation. Required for protein stability of MTOR and MTOR-related proteins, and cell cycle progress by growth factors.

Subunit / interactions. Part of the multiprotein complex composed of BRAT1, WDR73, as well as integrator complex subunits INTS9 and INTS11. Interacts with BRCA1 and ATM. Interacts with MTOR and RPTOR. Interacts with NDFIP1. Interacts with SMC1A and PRKDC.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Ubiquitinated by NEDD4, NEDD4L and ITCH; mono- and polyubiquitinated forms are detected.

Disease relevance. Rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL) [MIM:614498] A lethal, neonatal, neurologic disorder characterized by episodic jerking that is apparent in utero, lack of psychomotor development, axial and limb rigidity, frequent multifocal seizures, and dysautonomia. At birth, affected individuals have small heads, overlapping cranial sutures, small or absent fontanels, and depressed frontal bones. Infants show poorly responsive focal jerks of the tongue, face and arms in a nearly continuous sequence throughout life. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS) [MIM:618056] An autosomal recessive disorder characterized by psychomotor developmental delay manifesting in infancy, cerebellar atrophy, decreased myelination, and seizures in most patients. Additional features include intellectual disability, ataxia or dyspraxia, hypertonia, hyperreflexia, poor or absent speech, microcephaly, subtle dysmorphisms, and visual impairment in some patients. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The BRAT1-like motif mediates inhibition of the endonuclease activity of INTS11 by forming hydrogen bond and hydrophobic interactions with the active site of INTS11: Cys-820 coordinates one of the two active site zinc ions of INTS11.

Similarity. Belongs to the BRAT1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6PJG6-1	1	yes
Q6PJG6-2	2
Q6PJG6-3	3

RefSeq proteins (3): NP_001337555, NP_001337556, NP_689956* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000357	HEAT	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR038904	BRAT1	Family

Pfam: PF02985

UniProt features (82 total): helix 45, turn 9, sequence variant 7, strand 5, splice variant 4, repeat 2, mutagenesis site 2, sequence conflict 2, region of interest 2, chain 1, short sequence motif 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4IFI	X-RAY DIFFRACTION	2.2
8R23	ELECTRON MICROSCOPY	3.2
8UIB	ELECTRON MICROSCOPY	3.21
8R22	ELECTRON MICROSCOPY	3.9
8R2D	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PJG6-F1	85.28	0.55

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 (1): 820

Post-translational modifications (1): 742

Mutagenesis-validated functional residues (2):

Position	Phenotype
159	decreased interaction with ints11.
560	decreased interaction with ints11.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 220 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, chr7p22, MARTINEZ_RB1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_CELL_GROWTH, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_GLUCOSE_METABOLIC_PROCESS, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS

GO Biological Process (11): positive regulation of protein phosphorylation (GO:0001934), glucose metabolic process (GO:0006006), apoptotic process (GO:0006915), DNA damage response (GO:0006974), cell population proliferation (GO:0008283), response to ionizing radiation (GO:0010212), cell migration (GO:0016477), positive regulation of cell growth (GO:0030307), protein localization to nucleus (GO:0034504), mitochondrion localization (GO:0051646), integrator complex assembly (GO:0160234)

GO Molecular Function (2): ribonuclease inhibitor activity (GO:0008428), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
hexose metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
cellular process	1
response to radiation	1
cell motility	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
protein localization to organelle	1
organelle localization	1
protein-containing complex assembly	1
RNA nuclease activity	1
nuclease inhibitor activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRAT1	BRCA1	P38398	847
BRAT1	BRAP	Q7Z569	664
BRAT1	CT47B1	P0C2W7	514
BRAT1	ATM	Q13315	445
BRAT1	INCA1	Q0VD86	441
BRAT1	RLIG1	Q8N999	405
BRAT1	CARD19	Q96LW7	403
BRAT1	TONSL	Q96HA7	401
BRAT1	TUBGCP6	Q96RT7	385
BRAT1	TP53BP1	Q12888	371
BRAT1	KCNT1	Q5JUK3	370
BRAT1	FYTTD1	Q96QD9	369
BRAT1	CFAP53	Q96M91	348
BRAT1	THAP3	Q8WTV1	339
BRAT1	CDKN2D	P55273	335

IntAct

119 interactions, top by confidence:

A	B	Type	Score
INTS9	INTS11	psi-mi:“MI:0914”(association)	0.940
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PSMD7	PSMD11	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TNFSF13B	IPO8	psi-mi:“MI:0914”(association)	0.640
BRCA1	BRAT1	psi-mi:“MI:0915”(physical association)	0.600
BRCA1	BRAT1	psi-mi:“MI:0403”(colocalization)	0.600
BRAT1	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
BRAT1	USHBP1	psi-mi:“MI:0915”(physical association)	0.560
MSGN1	BRAT1	psi-mi:“MI:0915”(physical association)	0.560
NMI	BRAT1	psi-mi:“MI:0915”(physical association)	0.560
KLF11	BRAT1	psi-mi:“MI:0915”(physical association)	0.560
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
TMEM108	TCAF2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530

BioGRID (132): BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), BRAT1 (Affinity Capture-MS), RPTOR (Affinity Capture-Western), MTOR (Affinity Capture-Western), BRAT1 (Affinity Capture-MS)

ESM2 similar proteins: A0JN53, A2ACJ2, D2I4M3, D4ACE5, E9Q2M9, G3HQ82, O15360, O75161, P59240, Q0VG06, Q1T7C0, Q24JP3, Q3KNJ2, Q3U5Q7, Q3U6Q4, Q3UK37, Q3ZAU7, Q400C9, Q400G9, Q571B6, Q5F479, Q5SW28, Q5UE93, Q6AYI4, Q6PJG6, Q6ZS81, Q7Z412, Q8BGI5, Q8BVF9, Q8C0R7, Q8C3R1, Q8C3S2, Q8CC12, Q8CEC0, Q8IWY9, Q8IXR5, Q8TC57, Q8TE82, Q8TF30, Q8WXE1

Diamond homologs: D2I4M3, Q1RLU1, Q6PJG6, Q8C3R1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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.

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	17	5.1×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1389 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	76
Likely pathogenic	36
Uncertain significance	539
Likely benign	556
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031685	NM_152743.4(BRAT1):c.617T>A (p.Leu206Ter)	Pathogenic
1069574	NC_000007.13:g.(?2584533)(2594065_?)del	Pathogenic
1070797	NM_152743.4(BRAT1):c.1768C>T (p.Gln590Ter)	Pathogenic
1072484	NM_152743.4(BRAT1):c.2023del (p.Tyr675fs)	Pathogenic
1073449	NC_000007.13:g.(?2559496)(2594065_?)del	Pathogenic
1074999	NM_152743.4(BRAT1):c.1823del (p.Pro608fs)	Pathogenic
1172632	NM_152743.4(BRAT1):c.1654C>T (p.Gln552Ter)	Pathogenic
1324687	NM_152743.4(BRAT1):c.1996_1997del (p.Leu666fs)	Pathogenic
1324705	NM_152743.4(BRAT1):c.646C>T (p.Gln216Ter)	Pathogenic
1356724	NM_152743.4(BRAT1):c.1083_1095del (p.Gly363fs)	Pathogenic
1377471	NM_152743.4(BRAT1):c.1711C>T (p.Gln571Ter)	Pathogenic
1393495	NM_152743.4(BRAT1):c.34del (p.Leu12fs)	Pathogenic
1452250	NM_152743.4(BRAT1):c.1590del (p.Trp531fs)	Pathogenic
1453640	NM_152743.4(BRAT1):c.1007del (p.Gly336fs)	Pathogenic
1458549	NM_152743.4(BRAT1):c.920del (p.His307fs)	Pathogenic
1458796	NM_152743.4(BRAT1):c.2284C>T (p.Gln762Ter)	Pathogenic
180136	NM_152743.4(BRAT1):c.453_454insGAGAAGAT (p.Leu152fs)	Pathogenic
180137	NM_152743.4(BRAT1):c.176T>C (p.Leu59Pro)	Pathogenic
180138	NM_152743.4(BRAT1):c.962_963del (p.Leu321fs)	Pathogenic
180139	NM_152743.4(BRAT1):c.1177del (p.Ala393fs)	Pathogenic
1933360	NM_152743.4(BRAT1):c.560_561insCG (p.Asp190fs)	Pathogenic
1957621	NM_152743.4(BRAT1):c.280C>T (p.Gln94Ter)	Pathogenic
2030476	NM_152743.4(BRAT1):c.2075_2091del (p.Leu692fs)	Pathogenic
2080436	NM_152743.4(BRAT1):c.2104_2107dup (p.Phe703Ter)	Pathogenic
2110761	NM_152743.4(BRAT1):c.1486C>T (p.Gln496Ter)	Pathogenic
2114572	NM_152743.4(BRAT1):c.1461C>A (p.Cys487Ter)	Pathogenic
2131739	NM_152743.4(BRAT1):c.1414C>T (p.Gln472Ter)	Pathogenic
2183060	NM_152743.4(BRAT1):c.529C>T (p.Arg177Ter)	Pathogenic
2184776	NM_152743.4(BRAT1):c.566dup (p.Gly189_Asp190insTer)	Pathogenic
225028	NM_152743.4(BRAT1):c.803+1G>C	Pathogenic

SpliceAI

3397 predictions. Top by Δscore:

Variant	Effect	Δscore
7:2538763:CT:C	acceptor_gain	1.0000
7:2539539:CTCA:C	donor_loss	1.0000
7:2539540:TCACC:T	donor_loss	1.0000
7:2539541:CACCT:C	donor_loss	1.0000
7:2539542:A:T	donor_loss	1.0000
7:2539543:C:CA	donor_loss	1.0000
7:2539638:CAGCT:C	acceptor_gain	1.0000
7:2539639:AGCT:A	acceptor_gain	1.0000
7:2539641:CT:C	acceptor_gain	1.0000
7:2539643:C:CC	acceptor_gain	1.0000
7:2539643:CTA:C	acceptor_loss	1.0000
7:2539644:T:A	acceptor_loss	1.0000
7:2541294:TCAC:T	donor_loss	1.0000
7:2541295:CAC:C	donor_loss	1.0000
7:2541296:ACCT:A	donor_loss	1.0000
7:2541297:C:CA	donor_loss	1.0000
7:2541832:CAAGC:C	acceptor_gain	1.0000
7:2541834:AGC:A	acceptor_gain	1.0000
7:2541834:AGCC:A	acceptor_loss	1.0000
7:2541835:GC:G	acceptor_gain	1.0000
7:2541835:GCCTG:G	acceptor_loss	1.0000
7:2541836:CC:C	acceptor_gain	1.0000
7:2541836:CCTGG:C	acceptor_loss	1.0000
7:2541837:C:CC	acceptor_gain	1.0000
7:2541837:CTGGG:C	acceptor_loss	1.0000
7:2541845:C:CT	acceptor_gain	1.0000
7:2541845:C:T	acceptor_gain	1.0000
7:2541846:A:T	acceptor_gain	1.0000
7:2542210:GA:G	acceptor_gain	1.0000
7:2543685:CAGGG:C	donor_gain	1.0000

AlphaMissense

5228 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:2538591:C:A	W648C	0.990
7:2538591:C:G	W648C	0.990
7:2539267:A:T	V561D	0.990
7:2544972:A:G	W123R	0.990
7:2544972:A:T	W123R	0.990
7:2538593:A:G	W648R	0.988
7:2538593:A:T	W648R	0.988
7:2538714:G:C	F607L	0.988
7:2538714:G:T	F607L	0.988
7:2538716:A:G	F607L	0.988
7:2539599:C:A	W514C	0.987
7:2539599:C:G	W514C	0.987
7:2543916:A:C	F159L	0.987
7:2543916:A:T	F159L	0.987
7:2543918:A:G	F159L	0.987
7:2543922:G:C	S157R	0.986
7:2543922:G:T	S157R	0.986
7:2543924:T:G	S157R	0.986
7:2544963:C:G	G126R	0.986
7:2539256:C:G	A565P	0.984
7:2544981:G:T	R120S	0.980
7:2539257:A:C	S564R	0.979
7:2539257:A:T	S564R	0.979
7:2539259:T:G	S564R	0.979
7:2539591:C:A	R517M	0.978
7:2547381:G:C	F75L	0.978
7:2547381:G:T	F75L	0.978
7:2547383:A:G	F75L	0.978
7:2554337:A:G	L32P	0.978
7:2544962:C:T	G126D	0.977

dbSNP variants (sampled 300 via entrez): RS1000065182 (7:2549775 A>G), RS1000199553 (7:2546370 G>A), RS1000310903 (7:2546127 C>T), RS1000359087 (7:2542587 A>C), RS1000449521 (7:2551636 C>T), RS1000648556 (7:2547006 G>A), RS1000721789 (7:2552820 GCTCTGCCTC>G), RS1000793391 (7:2557044 C>G), RS1000866284 (7:2539350 T>C), RS1000896770 (7:2542460 G>T), RS1001158434 (7:2543084 C>T), RS1001248249 (7:2556849 G>A), RS1001292358 (7:2557053 G>A), RS1001343670 (7:2546623 T>C), RS1001456948 (7:2552664 T>A,C)

Disease associations

OMIM: gene MIM:614506 | disease phenotypes: MIM:614498, MIM:618056, MIM:609813

GenCC curated gene-disease

Disease	Classification	Inheritance
neonatal-onset encephalopathy with rigidity and seizures	Definitive	Autosomal recessive
neurodevelopmental disorder with cerebellar atrophy and with or without seizures	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
neonatal-onset encephalopathy with rigidity and seizures	Definitive	AR
neurodevelopmental disorder with cerebellar atrophy and with or without seizures	Definitive	AR

Mondo (5): neonatal-onset encephalopathy with rigidity and seizures (MONDO:0013784), neurodevelopmental disorder with cerebellar atrophy and with or without seizures (MONDO:0020841), spondylocostal dysostosis 3, autosomal recessive (MONDO:0012349), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Lethal neonatal spasticity-epileptic encephalopathy syndrome (Orphanet:435845), Autosomal recessive spondylocostal dysostosis (Orphanet:2311), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000283	Broad face
HP:0000286	Epicanthus
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000505	Visual impairment
HP:0000648	Optic atrophy
HP:0000713	Agitation
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001310	Dysmetria
HP:0001317	Abnormal cerebellum morphology
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001522	Death in infancy
HP:0001662	Bradycardia
HP:0002045	Hypothermia
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002079	Hypoplasia of the corpus callosum

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001762_492	Obesity-related traits	5.000000e-06
GCST90002401_447	Platelet distribution width	7.000000e-18

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005109	energy expenditure
EFO:0007984	platelet component distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 finite cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9YS	Ubigene HeLa BRAT1 KO	Cancer cell line	Female
CVCL_VP81	GM26045	Finite cell line	Male
CVCL_VP82	GM26046	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders