ABRAXAS1

Summary

ABRAXAS1 (abraxas 1, BRCA1 A complex subunit, HGNC:25829) is a protein-coding gene on chromosome 4q21.23, encoding BRCA1-A complex subunit Abraxas 1 (Q6UWZ7). Involved in DNA damage response and double-strand break (DSB) repair.

This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 84142 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 1,005 total — 10 pathogenic, 2 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_139076

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25829
Approved symbol	ABRAXAS1
Name	abraxas 1, BRCA1 A complex subunit
Location	4q21.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13614, ABRA1, ABRAXAS
Ensembl gene	ENSG00000163322
Ensembl biotype	protein_coding
OMIM	611143
Entrez	84142

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000321945, ENST00000475656, ENST00000503217, ENST00000504777, ENST00000505489, ENST00000506553, ENST00000511801, ENST00000515303, ENST00000611288, ENST00000856948, ENST00000856949, ENST00000856950, ENST00000917160, ENST00000917161, ENST00000949403

RefSeq mRNA: 2 — MANE Select: NM_139076 NM_001345962, NM_139076

CCDS: CCDS3605

Canonical transcript exons

ENST00000321945 — 9 exons

Exon	Start	End
ENSE00001702219	83484986	83485100
ENSE00001944316	83459517	83462902
ENSE00003500563	83469032	83469151
ENSE00003510267	83482154	83482244
ENSE00003528426	83472222	83472288
ENSE00003604224	83476643	83476679
ENSE00003673475	83470203	83470396
ENSE00003683984	83463494	83463608
ENSE00003791583	83467454	83467538

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 93.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9617 / max 338.3372, expressed in 1802 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52930	18.3817	1800
52931	0.5800	325

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.83	gold quality
calcaneal tendon	UBERON:0003701	93.36	gold quality
tendon	UBERON:0000043	92.03	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.30	gold quality
deltoid	UBERON:0001476	87.66	gold quality
vastus lateralis	UBERON:0001379	87.31	gold quality
tendon of biceps brachii	UBERON:0008188	87.14	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	86.99	gold quality
quadriceps femoris	UBERON:0001377	86.97	gold quality
monocyte	CL:0000576	86.76	gold quality
heart right ventricle	UBERON:0002080	86.71	gold quality
tibialis anterior	UBERON:0001385	86.61	gold quality
leukocyte	CL:0000738	86.49	gold quality
ovary	UBERON:0000992	86.39	gold quality
biceps brachii	UBERON:0001507	86.37	gold quality
left ovary	UBERON:0002119	86.32	gold quality
skeletal muscle tissue	UBERON:0001134	85.32	gold quality
bronchial epithelial cell	CL:0002328	84.83	gold quality
epithelial cell of pancreas	CL:0000083	84.37	silver quality
right ovary	UBERON:0002118	84.24	gold quality
bronchus	UBERON:0002185	83.96	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.76	gold quality
germinal epithelium of ovary	UBERON:0001304	83.67	gold quality
muscle tissue	UBERON:0002385	83.45	gold quality
endocervix	UBERON:0000458	83.02	gold quality
colonic epithelium	UBERON:0000397	82.97	gold quality
muscle of leg	UBERON:0001383	82.86	gold quality
endometrium	UBERON:0001295	82.77	gold quality
medial globus pallidus	UBERON:0002477	82.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting ABRAXAS1, 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-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• Abraxas and RAP80 were required for DNA damage resistance, G(2)-M checkpoint control, and DNA repair. (PMID:17525340)
• CCDC98 is a BRCA1 binding partner that mediates BRCA1 function in response to DNA damage. (PMID:17643121)
• CCDC98 is a mediator of BRCA1 function involved in the mammalian DNA damage response. (PMID:17643122)
• the human Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage (PMID:18077395)
• Mutational analysis in 168 multiple-case breast/ovarian cancer families, negative for mutations in BRCA1 or BRCA2, suggests that CCDC98 does not play an important role as a high penetrance breast cancer susceptibility gene. (PMID:18270812)
• it seems unlikely that moderate to highly penetrant alleles of either RAP80 or Abraxas, confer a significantly high relative risk of breast cancer. (PMID:18695986)
• examined RAP80 and Abraxas expression and their effect on treatment outcome in non-small-cell lung cancer (PMID:19415121)
• low expression correlates with better response to chemotherapy and longer survival in patients with advanced non small-cell lung cancer (PMID:21529986)
• The recurrent Abraxas c.1082G>A mutation connects to breast cancer predisposition. (PMID:22357538)
• Demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR. (PMID:26778126)
• Results identified 16 novel rare variants in FAM175A but no significant difference in allele frequencies between cases and controls was observed which suggest no evidence that rare variants in ABRAXAS are associated with increased breast cancer risk in the population studied. (PMID:27270457)
• Our data also suggest how ataxia telangiectasia mutated (ATM)-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex. (PMID:28009280)
• IN 96 BRCA1-negative breast cancer patients two missense variants: c.422C>T and c.1042G>A as well as two intronic variants: IVS3-34G>A, IVS3-44T>C were detected in the ABRAXAS1 gene. (PMID:30786683)
• the p.L243V variant of FAM175A may not be causative for premature ovarian insufficiency (PMID:31000350)
• Authors demonstrate in patient-derived cells that the Finnish ABRAXAS1 founder mutation (c.1082G > A, Arg361Gln), even in the heterozygous state leads to decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP. (PMID:31630195)
• ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways-lessons from breast cancer patients. (PMID:37198153)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	abraxas1	ENSDARG00000043339
mus_musculus	Abraxas1	ENSMUSG00000035234
rattus_norvegicus	Abraxas1	ENSRNOG00000002165

Paralogs (1): ABRAXAS2 (ENSG00000165660)

Protein

Protein identifiers

BRCA1-A complex subunit Abraxas 1 — Q6UWZ7 (reviewed: Q6UWZ7)

Alternative names: Coiled-coil domain-containing protein 98, Protein FAM175A

All UniProt accessions (8): A0A087WWJ9, A0A087WXK1, A0A087WZ78, Q6UWZ7, D6RAN3, D6REL5, D6RHI5, E9PHB9

UniProt curated annotations — full annotation on UniProt →

Function. Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes ‘Lys-63’-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes ‘Lys-63’-linked ubiquitin on histones H2A and H2AX.

Subunit / interactions. Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the complex, interacts directly with UIMC1/RAP80, BRCC3/BRCC36 and BABAM2. Interacts directly (when phosphorylated at Ser-406) with BRCA1. Homodimer. The homodimer interacts directly (when phosphorylated at Ser-404 and Ser-406) with two BRCA1 chains, giving rise to a heterotetramer. Binds polyubiquitin.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylation of Ser-406 of the pSXXF motif by ATM or ATR constitutes a specific recognition motif for the BRCT domain of BRCA1. Ionizing radiation promotes rapid phosphorylation at Ser-404 and Ser-406 by ATM; this promotes recruitment of BRCA1 to sites of DNA damage.

Disease relevance. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the FAM175 family. Abraxas subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UWZ7-1	1	yes
Q6UWZ7-2	2

RefSeq proteins (2): NP_001332891, NP_620775* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023238	FAM175	Family
IPR023239	BRISC_Abraxas1	Family
IPR037518	MPN	Domain

Pfam: PF21125

UniProt features (25 total): mutagenesis site 7, modified residue 6, sequence variant 4, compositionally biased region 2, chain 1, domain 1, splice variant 1, region of interest 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4Y2G	X-RAY DIFFRACTION	2.5
4JLU	X-RAY DIFFRACTION	3.5
4Y18	X-RAY DIFFRACTION	3.5
4U4A	X-RAY DIFFRACTION	3.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWZ7-F1	77.10	0.48

Functional residue map

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

Post-translational modifications (6): 390, 404, 406, 48, 386, 387

Mutagenesis-validated functional residues (7):

Position	Phenotype
400	no effect on formation of a heterotetramer with brca1.
402	decreases formation of a heterotetramer with brca1.
403	no effect on formation of a heterotetramer with brca1.
404	no effect on homodimerization. mildly decreased recruitment of brca1 to sites of dna damage.
404	permits formation of a heterotetramer with brca1.
404	abolishes formation of a heterotetramer with brca1. does not affect interaction with a first brca1 chain.
406	abolishes phosphorylation of the psxxf motif and the interaction with brca1 but does not affect the interaction with uim

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-5689901	Metalloprotease DUBs
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-1640170	Cell Cycle
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-5693606	DNA Double Strand Break Response
R-HSA-597592	Post-translational protein modification
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73894	DNA Repair

MSigDB gene sets: 155 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_RESPONSE_TO_IONIZING_RADIATION, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_MITOTIC_SPINDLE_ASSEMBLY, GOBP_ORGANELLE_FISSION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_NUCLEAR_DIVISION

GO Biological Process (11): regulation of DNA repair (GO:0006282), double-strand break repair (GO:0006302), chromatin organization (GO:0006325), mitotic G2 DNA damage checkpoint signaling (GO:0007095), attachment of spindle microtubules to kinetochore (GO:0008608), response to ionizing radiation (GO:0010212), mitotic G2/M transition checkpoint (GO:0044818), positive regulation of DNA repair (GO:0045739), mitotic spindle assembly (GO:0090307), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (3): microtubule binding (GO:0008017), polyubiquitin modification-dependent protein binding (GO:0031593), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), BRCA1-A complex (GO:0070531)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
DNA Double-Strand Break Repair	3
Deubiquitination	1
DNA Double Strand Break Response	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
G2/M Checkpoints	1
Post-translational protein modification	1
DNA Repair	1
Homology Directed Repair	1
Metabolism of proteins	1
Cell Cycle Checkpoints	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA repair	3
regulation of DNA metabolic process	1
regulation of cellular response to stress	1
cellular component organization	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
microtubule binding	1
cell cycle process	1
metaphase chromosome alignment	1
response to radiation	1
mitotic cell cycle checkpoint signaling	1
negative regulation of G2/M transition of mitotic cell cycle	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
mitotic sister chromatid segregation	1
mitotic spindle organization	1
spindle assembly	1
mitotic nuclear division	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
tubulin binding	1
modification-dependent protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABRAXAS1	UIMC1	Q96RL1	999
ABRAXAS1	BRCC3	P46736	998
ABRAXAS1	BABAM2	Q9NXR7	997
ABRAXAS1	BABAM1	Q9NWV8	997
ABRAXAS1	BRCA1	P38398	997
ABRAXAS1	BARD1	Q99728	993
ABRAXAS1	BRCA2	P51587	754
ABRAXAS1	MDC1	Q14676	748
ABRAXAS1	RBBP8	Q99708	729
ABRAXAS1	RAD51C	O43502	712
ABRAXAS1	RAD51D	O75771	712
ABRAXAS1	K7EN88	K7EN88	706
ABRAXAS1	RNF8	O76064	705
ABRAXAS1	PALB2	Q86YC2	699
ABRAXAS1	MRE11	P49959	691

IntAct

54 interactions, top by confidence:

A	B	Type	Score
BRCA1	ABRAXAS1	psi-mi:“MI:0407”(direct interaction)	0.860
BRCA1	ABRAXAS1	psi-mi:“MI:0915”(physical association)	0.860
ABRAXAS1	BRCA1	psi-mi:“MI:0403”(colocalization)	0.860
ABRAXAS1	BRCA1	psi-mi:“MI:0914”(association)	0.860
BRCA1	ABRAXAS1	psi-mi:“MI:0914”(association)	0.860
ABRAXAS1	BRCA1	psi-mi:“MI:0915”(physical association)	0.860
UIMC1	BRCA1	psi-mi:“MI:0914”(association)	0.780
ABRAXAS1	UIMC1	psi-mi:“MI:0915”(physical association)	0.680
UIMC1	ABRAXAS1	psi-mi:“MI:0915”(physical association)	0.680
ABRAXAS1	UIMC1	psi-mi:“MI:0915”(physical association)	0.660
UIMC1	ABRAXAS1	psi-mi:“MI:0915”(physical association)	0.660
ABRAXAS1	BRCC3	psi-mi:“MI:0915”(physical association)	0.640
BABAM1	TNKS	psi-mi:“MI:0914”(association)	0.640

BioGRID (187): FAM175A (Affinity Capture-Western), FAM175A (Affinity Capture-MS), LAMC1 (Affinity Capture-MS), WTAP (Affinity Capture-MS), FAM175A (Affinity Capture-MS), FAM175A (Affinity Capture-MS), FAM175A (Affinity Capture-MS), FAM175A (Affinity Capture-Western), FAM175A (Affinity Capture-Western), FAM175A (Affinity Capture-Western), FAM175A (Affinity Capture-MS), PSMC5 (Affinity Capture-MS), FAM175A (Affinity Capture-MS), FAM175A (Affinity Capture-MS), WTAP (Affinity Capture-MS)

ESM2 similar proteins: A0A8M3AJY3, A5WUN7, A6QLR3, B5X1P9, E2AB17, F1MJR8, F1QB81, M0R5D6, O00443, O43310, O60291, P03122, P11299, P15304, P42859, P51111, P59438, Q15018, Q1HKZ5, Q1LUT1, Q1LVP6, Q28HX0, Q2PFD7, Q2T9I9, Q3TCJ1, Q3TEL6, Q3UPF5, Q535K8, Q5E9P1, Q5I0F1, Q5RD34, Q5VUB5, Q5XIQ4, Q5ZHS0, Q61194, Q6GR31, Q6INH1, Q6P4W0, Q6PEE2, Q6UWZ7

Diamond homologs: A0A8M3AJY3, A6QLR3, B5X1P9, Q15018, Q1LVP6, Q28HX0, Q3TCJ1, Q5E9P1, Q5I0F1, Q5ZHS0, Q6GR31, Q6P4W0, Q6UWZ7, Q8BPZ8, E2AB17

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ABRAXAS1	up-regulates	BRCA1	binding
ATM	“up-regulates activity”	ABRAXAS1	phosphorylation
ABRAXAS1	“form complex”	“BRCA1-A complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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
Metalloprotease DUBs	6	82.0×	1e-08
Nonhomologous End-Joining (NHEJ)	6	45.8×	1e-07
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	6	39.9×	3e-07
G2/M DNA damage checkpoint	7	38.2×	4e-08
G2/M Checkpoints	6	36.6×	4e-07
Processing of DNA double-strand break ends	7	36.3×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
mitotic G2/M transition checkpoint	6	200.6×	5e-11
mitotic G2 DNA damage checkpoint signaling	5	92.4×	1e-07
positive regulation of DNA repair	6	89.6×	5e-09
response to ionizing radiation	5	85.6×	1e-07
cellular response to ionizing radiation	5	85.6×	1e-07
regulation of DNA repair	5	57.5×	6e-07
double-strand break repair	6	50.8×	1e-07
DNA damage response	5	11.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1005 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	2
Uncertain significance	609
Likely benign	282
Benign	38

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
147709	GRCh38/hg38 4q21.21-21.23(chr4:79786514-85832807)x1	Pathogenic
151718	GRCh38/hg38 4q21.21-21.3(chr4:80043949-86948317)x1	Pathogenic
1708193	GRCh37/hg19 4q21.22-21.23(chr4:84048377-84744105)x1	Pathogenic
2426212	NC_000004.11:g.(?84185352)(84406225_?)del	Pathogenic
57143	GRCh38/hg38 4q21.1-21.23(chr4:75453111-84094295)x1	Pathogenic
625784	GRCh37/hg19 4q21.21-22.1(chr4:82043901-88334228)	Pathogenic
686225	GRCh37/hg19 4q21.1-21.23(chr4:78769297-84968832)x1	Pathogenic
814566	GRCh37/hg19 4q13.3-21.23(chr4:72680879-86426232)x1	Pathogenic
814576	GRCh37/hg19 4q21.22-21.23(chr4:82593140-85651685)x1	Pathogenic
983172	GRCh37/hg19 4q13.3-21.3(chr4:71412409-87920784)x1	Pathogenic
148797	GRCh38/hg38 4q21.21-21.23(chr4:80908016-84329610)x1	Likely pathogenic
155254	GRCh38/hg38 4q21.22-21.23(chr4:81675848-83970410)x1	Likely pathogenic

SpliceAI

1890 predictions. Top by Δscore:

Variant	Effect	Δscore
4:83459721:A:AG	acceptor_gain	1.0000
4:83459723:A:AG	acceptor_gain	1.0000
4:83459724:T:G	acceptor_gain	1.0000
4:83459725:A:AG	acceptor_gain	1.0000
4:83459726:A:G	acceptor_gain	1.0000
4:83460967:TTACA:T	acceptor_loss	1.0000
4:83460968:TACA:T	acceptor_loss	1.0000
4:83460969:ACAGG:A	acceptor_loss	1.0000
4:83460970:CA:C	acceptor_loss	1.0000
4:83460971:AGG:A	acceptor_loss	1.0000
4:83460972:G:A	acceptor_loss	1.0000
4:83463488:ACTT:A	donor_loss	1.0000
4:83463489:CTT:C	donor_loss	1.0000
4:83463490:TTAC:T	donor_loss	1.0000
4:83463491:TACTT:T	donor_loss	1.0000
4:83463492:A:AC	donor_gain	1.0000
4:83463492:A:T	donor_loss	1.0000
4:83463493:C:A	donor_loss	1.0000
4:83463493:C:CA	donor_gain	1.0000
4:83463493:CTTG:C	donor_gain	1.0000
4:83467447:AACTT:A	donor_loss	1.0000
4:83467448:ACTT:A	donor_loss	1.0000
4:83467449:CTTAC:C	donor_loss	1.0000
4:83467450:TTA:T	donor_loss	1.0000
4:83467451:T:TG	donor_loss	1.0000
4:83467453:C:CG	donor_loss	1.0000
4:83470201:AC:A	donor_gain	1.0000
4:83470202:CC:C	donor_gain	1.0000
4:83482147:AACTC:A	donor_loss	1.0000
4:83482148:ACT:A	donor_loss	1.0000

AlphaMissense

2729 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:83470384:A:G	W99R	0.999
4:83470384:A:T	W99R	0.999
4:83470371:C:G	R103P	0.997
4:83470386:C:T	G98D	0.997
4:83470387:C:G	G98R	0.997
4:83482193:C:G	D47H	0.997
4:83482237:A:G	F32S	0.997
4:83482241:C:G	G31R	0.997
4:83482192:T:C	D47G	0.996
4:83470372:G:T	R103S	0.995
4:83482191:A:C	D47E	0.995
4:83482191:A:T	D47E	0.995
4:83482192:T:A	D47V	0.995
4:83482192:T:G	D47A	0.995
4:83482228:C:T	G35E	0.995
4:83482229:C:A	G35W	0.994
4:83482229:C:G	G35R	0.994
4:83482229:C:T	G35R	0.994
4:83485027:C:G	G16R	0.994
4:83482234:A:G	L33P	0.993
4:83482240:C:T	G31D	0.993
4:83485039:C:G	G12R	0.993
4:83470278:A:G	L134P	0.992
4:83470281:A:G	L133P	0.992
4:83470338:T:A	E114V	0.992
4:83470381:A:C	Y100D	0.992
4:83470382:C:A	W99C	0.991
4:83470382:C:G	W99C	0.991
4:83485038:C:T	G12D	0.991
4:83470383:C:G	W99S	0.990

dbSNP variants (sampled 300 via entrez): RS1000245669 (4:83471871 A>G), RS1000298100 (4:83459086 C>G,T), RS1000319709 (4:83471553 T>C), RS1000522941 (4:83474508 T>A,C), RS1000554046 (4:83474326 G>A), RS1000729398 (4:83468149 T>C), RS1000800665 (4:83469709 A>G), RS1000897078 (4:83485810 G>A), RS1001023838 (4:83477303 A>G), RS1001094107 (4:83486048 G>C), RS1001336035 (4:83479196 T>A,C), RS1001473553 (4:83485028 G>A,T), RS1001495954 (4:83476971 G>A), RS1001546832 (4:83460092 A>G), RS1001617235 (4:83466409 C>G,T)

Disease associations

OMIM: gene MIM:611143 | disease phenotypes:

GenCC curated gene-disease

Mondo (3): hereditary neoplastic syndrome (MONDO:0015356), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast cancer (MONDO:0007254)

Orphanet (2): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001011_5	Oral cavity and pharyngeal cancer	1.000000e-08
GCST005312_10	Menopause (age at onset)	9.000000e-23
GCST009391_1561	Metabolite levels	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0009776	ornithine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Valproic Acid	decreases expression, increases expression	3
bisphenol A	increases methylation, increases expression	2
sodium arsenite	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, 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	decreases expression	1
Sunitinib	increases expression	1
Caffeine	decreases phosphorylation	1
Coumestrol	decreases expression	1
Melphalan	decreases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	increases expression	1
Monocrotaline	decreases expression, increases metabolic processing	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM89	HAP1 FAM175A (-) 1	Cancer cell line	Male
CVCL_SM90	HAP1 FAM175A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer