TMC6

Summary

TMC6 (transmembrane channel like 6, HGNC:18021) is a protein-coding gene on chromosome 17q25.3, encoding Transmembrane channel-like protein 6 (Q7Z403). Acts as a regulatory protein involved in the regulation of numerous cellular processes.

Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs.

Source: NCBI Gene 11322 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermodysplasia verruciformis, susceptibility to, 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 48
• Clinical variants (ClinVar): 875 total — 29 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 14
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001127198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18021
Approved symbol	TMC6
Name	transmembrane channel like 6
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	LAK-4P, EVIN1
Ensembl gene	ENSG00000141524
Ensembl biotype	protein_coding
OMIM	605828
Entrez	11322

Gene structure

Transcript identifiers

Ensembl transcripts: 112 — 88 protein_coding, 13 retained_intron, 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay

ENST00000306591, ENST00000322914, ENST00000392467, ENST00000585849, ENST00000586126, ENST00000586271, ENST00000586697, ENST00000587480, ENST00000588087, ENST00000588792, ENST00000589217, ENST00000589271, ENST00000589553, ENST00000589933, ENST00000590162, ENST00000590494, ENST00000590602, ENST00000590934, ENST00000591594, ENST00000591756, ENST00000592063, ENST00000592076, ENST00000592594, ENST00000593044, ENST00000698544, ENST00000698545, ENST00000698546, ENST00000698547, ENST00000698548, ENST00000698549, ENST00000698550, ENST00000698551, ENST00000893453, ENST00000893454, ENST00000893455, ENST00000893456, ENST00000893457, ENST00000893458, ENST00000893459, ENST00000893460, ENST00000893461, ENST00000893462, ENST00000893463, ENST00000893464, ENST00000893465, ENST00000893466, ENST00000893467, ENST00000893468, ENST00000893469, ENST00000893470, ENST00000893471, ENST00000893472, ENST00000893473, ENST00000893474, ENST00000893475, ENST00000893476, ENST00000893477, ENST00000893478, ENST00000893479, ENST00000893480, ENST00000893481, ENST00000893482, ENST00000893483, ENST00000893484, ENST00000893485, ENST00000893486, ENST00000893487, ENST00000893488, ENST00000893489, ENST00000893490, ENST00000893491, ENST00000893492, ENST00000893493, ENST00000893494, ENST00000893495, ENST00000893496, ENST00000893497, ENST00000893498, ENST00000893499, ENST00000893500, ENST00000893501, ENST00000893502, ENST00000922735, ENST00000922736, ENST00000922737, ENST00000922738, ENST00000922739, ENST00000922740, ENST00000922741, ENST00000922742, ENST00000922743, ENST00000922744, ENST00000922745, ENST00000922746, ENST00000922747, ENST00000922748, ENST00000972370, ENST00000972371, ENST00000972372, ENST00000972373, ENST00000972374, ENST00000972375, ENST00000972376, ENST00000972377, ENST00000972378, ENST00000972379, ENST00000972380, ENST00000972381, ENST00000972382, ENST00000972383, ENST00000972384, ENST00000972385

RefSeq mRNA: 8 — MANE Select: NM_001127198 NM_001127198, NM_001321185, NM_001374593, NM_001374594, NM_001374596, NM_001375353, NM_001375354, NM_007267

CCDS: CCDS32748, CCDS92404

Canonical transcript exons

ENST00000590602 — 20 exons

Exon	Start	End
ENSE00002845926	78107397	78113211
ENSE00002864168	78128612	78128755
ENSE00003479171	78117269	78117347
ENSE00003482408	78121556	78121711
ENSE00003549600	78121013	78121164
ENSE00003550935	78119297	78119392
ENSE00003551574	78120653	78120832
ENSE00003554861	78126277	78126366
ENSE00003563512	78117468	78117644
ENSE00003564863	78124889	78124985
ENSE00003573648	78113548	78113624
ENSE00003579700	78117802	78117935
ENSE00003585551	78122605	78122749
ENSE00003593893	78126777	78126906
ENSE00003594520	78126524	78126648
ENSE00003636150	78123989	78124179
ENSE00003646190	78124524	78124781
ENSE00003676961	78118971	78119046
ENSE00003677498	78125158	78125263
ENSE00003785380	78125726	78125884

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3930 / max 1465.4021, expressed in 1373 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168340	13.5129	1266
168338	6.2755	1051
168339	3.3101	860
168343	1.0392	238
168332	0.9066	194
168341	0.6736	387
168337	0.6082	270
168331	0.5770	150
168342	0.2279	92
168336	0.1326	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.22	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.25	gold quality
lymph node	UBERON:0000029	98.12	gold quality
spleen	UBERON:0002106	98.06	gold quality
spinal cord	UBERON:0002240	97.44	gold quality
apex of heart	UBERON:0002098	97.02	gold quality
sural nerve	UBERON:0015488	96.72	gold quality
upper lobe of left lung	UBERON:0008952	96.63	gold quality
mucosa of transverse colon	UBERON:0004991	96.62	gold quality
buccal mucosa cell	CL:0002336	96.36	gold quality
vermiform appendix	UBERON:0001154	95.99	gold quality
right lung	UBERON:0002167	95.94	gold quality
upper lobe of lung	UBERON:0008948	95.89	gold quality
caecum	UBERON:0001153	95.88	gold quality
colonic epithelium	UBERON:0000397	95.73	gold quality
blood	UBERON:0000178	95.67	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.29	gold quality
bone marrow cell	CL:0002092	94.86	gold quality
lateral globus pallidus	UBERON:0002476	94.80	gold quality
tibial nerve	UBERON:0001323	94.71	gold quality
inferior vagus X ganglion	UBERON:0005363	94.70	gold quality
leukocyte	CL:0000738	94.67	gold quality
omental fat pad	UBERON:0010414	94.67	gold quality
peritoneum	UBERON:0002358	94.66	gold quality
cardia of stomach	UBERON:0001162	94.63	gold quality
monocyte	CL:0000576	94.51	gold quality
mononuclear cell	CL:0000842	94.48	gold quality
minor salivary gland	UBERON:0001830	94.45	gold quality
tonsil	UBERON:0002372	94.38	gold quality
subthalamic nucleus	UBERON:0001906	94.29	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.82
E-CURD-112	yes	4.88
E-MTAB-7606	no	2028.92
E-ENAD-27	no	4.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting TMC6, 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-4267	99.96	66.53	2368
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-34A-3P	96.80	67.70	805

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• Mutations in EVER1 are associated with epidermodysplasia verruciformis. (PMID:12426567)
• Nonsense mutations of EVER1gene is associated with epidermodysplasia verruciformis (PMID:15042430)
• four mutations in recurrent respiratory papillomatosis patients might indicate that EVER 1 alleles are not associated with susceptibility to RRP (PMID:16487602)
• The growing number of mutations in epidermodysplasia verruciformis (EV) pedigrees supports the hypothesis that EVER1 and EVER2 are the molecular basis of EV. (PMID:17008061)
• HPV16 E5 protein binds to EVER and ZnT-1 and blocks their negative regulation (PMID:18158319)
• epidermodysplasia verruciformis in a father and a son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 (PMID:19706093)
• Data support the involvement of the TMC6/8 region in cervix cancer susceptibility. (PMID:21387292)
• EVER proteins appear as key components of the activation-dependent regulation of Zn(2+) concentration in T cells. However, the impact of EVER-deficiency in T cells on EV pathogenesis remains to be elucidated (PMID:22761942)
• EV is also a rare autosomal recessive genodermatosis involving susceptibility to human papillomavirus (HPV) infections and squamous cell carcinoma, caused in most cases by homozygous mutations in EVER1 or EVER2. (PMID:23534907)
• We report a case of Merkel cell polyomavirus detection in the skin of a patient with epidermodysplasia verruciformis (EDV) and a family history remarkable for an unusual inheritance pattern for EDV. (PMID:23535066)
• Expression of both EVER1 and EVER2 in B cells is activated immediately after Epstein-Barr virus (EBV) infection, whereas at later stages, it is strongly repressed by latent membrane protein 1-activated NF-kappaB signaling. (PMID:25378492)
• TMC6 variants are associated with diminished age-of-onset of P. aeruginosa airway infection in children with cystic fibrosis. (PMID:26047157)
• Findings suggest that SNP in EVER 1 may be involved in the development of premalignant skin lesions that harbour beta-HPV, perhaps giving rise to SCC tumours that have lost beta-HPV gene expression during progression (PMID:26126409)
• TMC6/EVER1 and TMC8/EVER2 are known to be involved in the development of EV. (PMID:26227733)
• There were no differences in Ever1 SNPs between head and neck squamous cell carcinoma patients with human papilloma virus (HPV)-positive and HPV-negative tumors, and healthy controls. (PMID:27097911)
• The present study did not show any significant association of the EVER1/2 polymorphisms (rs2290907and rs16970849) with cervical cancer. (PMID:27899077)
• LncRNA TNRC6C-AS1 regulates UNC5B in thyroid cancer to influence cell proliferation, migration, and invasion as a competing endogenous RNA of miR-129-5p. (PMID:29893424)
• these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to beta-HPVs of epidermodysplasia verruciformis patients. (PMID:30068544)
• Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components. (PMID:32917726)
• A Novel Large Deletion in the EVER1 Gene in a Family With Epidermodysplasia Verruciformis From India. (PMID:38574087)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmc6a	ENSDARG00000069787
mus_musculus	Tmc6	ENSMUSG00000025572
rattus_norvegicus	Tmc6	ENSRNOG00000053469
caenorhabditis_elegans		WBGENE00015177
caenorhabditis_elegans		WBGENE00020490

Paralogs (7): TMC5 (ENSG00000103534), TMC2 (ENSG00000149488), TMC1 (ENSG00000165091), TMC4 (ENSG00000167608), TMC8 (ENSG00000167895), TMC7 (ENSG00000170537), TMC3 (ENSG00000188869)

Protein

Protein identifiers

Transmembrane channel-like protein 6 — Q7Z403 (reviewed: Q7Z403)

Alternative names: Epidermodysplasia verruciformis protein 1, Protein LAK-4

All UniProt accessions (8): A0A8V8TLU9, A0A8V8TLY1, A0A8V8TME3, A0A8V8TND2, Q7Z403, K7ELP1, K7ENC4, K7ERH0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a regulatory protein involved in the regulation of numerous cellular processes. Together with its homolog TMC8/EVER2, forms a complex with CIB1 in lymphocytes and keratynocytes where TMC6 and TMC8 stabilize CIB1 and reciprocally. Together with TMC8, also forms a complex with and activates zinc transporter ZNT1 at the ER membrane of keratynocytes, thereby facilitating zinc uptake into the ER. Down-regulates the activity of transcription factors induced by zinc and cytokines. Also plays a role in thermal sensation by inhibiting the M-channel (KCNQ2-KCNQ3 channel) current in primary sensory neurons.

Subunit / interactions. Interacts with TMC8. Interacts and forms a complex with TMC8 and CIB1; the interaction stabilizes each component of the complex. Interacts and forms a complex with TMC8 and SLC30A1/ZNT1; the interaction regulates zinc transport into the ER. (Microbial infection) Interacts with human papillomavirus 16/HPV16 protein E5; the interaction alleviates TMC6-mediated transcription factors inhibition.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Nucleus membrane.

Tissue specificity. Expressed in placenta, prostate, testis, activated T-lymphocytes and lymphokine-activated killer (LAK) lymphocytes.

Disease relevance. Epidermodysplasia verruciformis 1 (EV1) [MIM:226400] A form of epidermodysplasia verruciformis, a rare genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses, including the oncogenic HPV5. Infection leads to the early development of disseminated flat wart-like and pityriasis versicolor-like skin lesions. Cutaneous Bowen’s carcinomas in situ and invasive squamous cell carcinomas develop in about half of the patients, mainly on sun-exposed skin areas. EV1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TMC family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q7Z403-1	1, Large EVER1	yes
Q7Z403-2	2, Small EVER1
Q7Z403-3	3
Q7Z403-4	4

RefSeq proteins (8): NP_001120670, NP_001308114, NP_001361522, NP_001361523, NP_001361525, NP_001362282, NP_001362283, NP_009198 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

UniProt features (41 total): topological domain 11, transmembrane region 10, splice variant 6, modified residue 3, sequence variant 3, sequence conflict 3, region of interest 2, glycosylation site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z403-F1	72.56	0.24

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 (3): 89, 94, 105

Glycosylation sites (2): 103, 312

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 231 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_CASP8, GOCC_SECRETORY_GRANULE, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, ZHAN_MULTIPLE_MYELOMA_CD1_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_PROTEIN_STABILIZATION, GOBP_REGULATION_OF_PROTEIN_STABILITY, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOBP_MONOATOMIC_ION_HOMEOSTASIS, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (3): intracellular zinc ion homeostasis (GO:0006882), protein stabilization (GO:0050821), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (2): mechanosensitive monoatomic ion channel activity (GO:0008381), protein binding (GO:0005515)

GO Cellular Component (12): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), specific granule membrane (GO:0035579), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
organelle membrane	2
secretory granule membrane	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
regulation of protein stability	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion channel activity	1
gated channel activity	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
nucleus	1
nuclear envelope	1
specific granule	1
extracellular vesicle	1
tertiary granule	1

Protein interactions and networks

STRING

1978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC6	SLC30A1	Q9Y6M5	969
TMC6	SYNGR2	O43760	902
TMC6	STAT3	P40763	891
TMC6	EZH2	Q15910	846
TMC6	HAVCR2	Q8TDQ0	774
TMC6	CANX	P27824	733
TMC6	TK1	P04183	712
TMC6	NPM1	P06748	665
TMC6	TMC8	Q8IU68	642
TMC6	CIB1	Q99828	607
TMC6	CTNNB1	P35222	602
TMC6	TP53	P04637	596
TMC6	HNRNPL	P14866	562
TMC6	ROCK1	Q13464	550
TMC6	HNRNPU	Q00839	535

IntAct

32 interactions, top by confidence:

A	B	Type	Score
TMC6	ZBTB2	psi-mi:“MI:0915”(physical association)	0.560
TMC6	PECAM1	psi-mi:“MI:0915”(physical association)	0.560
VIM	TMC6	psi-mi:“MI:0915”(physical association)	0.560
TMC6	JPH3	psi-mi:“MI:0915”(physical association)	0.560
TMC6	CCR9	psi-mi:“MI:0915”(physical association)	0.370
ZDHHC17	TMC6	psi-mi:“MI:0915”(physical association)	0.370
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TMC6	PXK	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
GP9	ESYT2	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
TTMP	NBAS	psi-mi:“MI:0914”(association)	0.350
KCNE3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SGCA	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	FAAH	psi-mi:“MI:0914”(association)	0.350
GP5	MGST3	psi-mi:“MI:0914”(association)	0.350
B4GAT1	KCNN4	psi-mi:“MI:0914”(association)	0.350
OR1D4	PROM1	psi-mi:“MI:0914”(association)	0.350
FASLG	TIPRL	psi-mi:“MI:0914”(association)	0.350
TMC6	LRRC8E	psi-mi:“MI:0914”(association)	0.350
ZBTB2	TMC6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (42): TMC6 (Two-hybrid), PXK (Affinity Capture-MS), C19orf26 (Affinity Capture-MS), TMC6 (Affinity Capture-RNA), TMC6 (Affinity Capture-RNA), TMC6 (Affinity Capture-RNA), ZBTB2 (Two-hybrid), TMC6 (Proximity Label-MS), TMC6 (Proximity Label-MS), TMC6 (Two-hybrid), TMC6 (Affinity Capture-RNA), TMC6 (Affinity Capture-RNA), TMC6 (Affinity Capture-MS), C19orf26 (Affinity Capture-MS), PXK (Affinity Capture-MS)

ESM2 similar proteins: A1A4P6, A1A5B4, A5PK40, A6NDV4, A6NFX1, A6NGC4, A6QL84, A6QLK4, B1AWJ5, B6ID01, E1BY51, P58749, Q2TA01, Q2YDG0, Q32PG7, Q3T9M1, Q4R7X9, Q5HZE5, Q5JZQ7, Q5R6H1, Q5RBY7, Q60HE8, Q6AY05, Q6AYM9, Q6PHN7, Q6TCG5, Q6UX01, Q6UXD7, Q7RTT9, Q7Z403, Q80ZE4, Q8CE47, Q8R139, Q8TBR7, Q96FZ5, Q96HE8, Q96S97, Q9BSA9, Q9BZW5, Q9CQC4

Diamond homologs: D3KZG3, E7FFT2, F1QFU0, F1QZE9, Q11069, Q32NZ6, Q5M7W4, Q5YCC7, Q6UXY8, Q7TN60, Q7TQ69, Q7Z403, Q7Z5M5, Q8R4P4, Q8R4P5, Q8TDI7, Q8TDI8, A0A0U1QT59

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	8
Uncertain significance	362
Likely benign	366
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076199	NM_001127198.5(TMC6):c.1942_1943del (p.Met648fs)	Pathogenic
1437451	NM_001127198.5(TMC6):c.1177C>T (p.Gln393Ter)	Pathogenic
1452246	NM_001127198.5(TMC6):c.1146dup (p.Val383fs)	Pathogenic
1454263	NM_001127198.5(TMC6):c.711_715del (p.Ile237fs)	Pathogenic
1455852	NM_001127198.5(TMC6):c.190C>T (p.Gln64Ter)	Pathogenic
1456110	NM_001127198.5(TMC6):c.2033C>A (p.Ser678Ter)	Pathogenic
1460287	NM_001127198.5(TMC6):c.2211C>A (p.Tyr737Ter)	Pathogenic
1921332	NM_001127198.5(TMC6):c.1053_1056del (p.Phe351fs)	Pathogenic
2015434	NM_001127198.5(TMC6):c.1698del (p.Phe566fs)	Pathogenic
2027415	NM_001127198.5(TMC6):c.1354del (p.Val452fs)	Pathogenic
2694155	NM_001127198.5(TMC6):c.846_855dup (p.Pro286fs)	Pathogenic
2809066	NC_000017.11:g.78121677_78121714del	Pathogenic
2811249	NM_001127198.5(TMC6):c.115C>T (p.Gln39Ter)	Pathogenic
2878605	NM_001127198.5(TMC6):c.2266C>T (p.Gln756Ter)	Pathogenic
3013473	NM_001127198.5(TMC6):c.1162del (p.Asp388fs)	Pathogenic
3242828	NC_000017.10:g.(?76120014)(76120748_?)del	Pathogenic
3655284	NM_001127198.5(TMC6):c.1996_1999del (p.Val666fs)	Pathogenic
4723363	NM_001127198.5(TMC6):c.1909C>T (p.Gln637Ter)	Pathogenic
4729464	NM_001127198.5(TMC6):c.160C>T (p.Gln54Ter)	Pathogenic
4745192	NM_001127198.5(TMC6):c.2130G>A (p.Trp710Ter)	Pathogenic
4748	NM_001127198.5(TMC6):c.280C>T (p.Arg94Ter)	Pathogenic
4750	NM_001127198.5(TMC6):c.744C>A (p.Tyr248Ter)	Pathogenic
4751	NM_001127198.5(TMC6):c.892-2A>T	Pathogenic
4762544	NM_001127198.5(TMC6):c.1423dup (p.Leu475fs)	Pathogenic
526234	NM_001127198.5(TMC6):c.1325dup (p.Thr444fs)	Pathogenic
582588	NM_001127198.5(TMC6):c.748_1082+56del	Pathogenic
662928	NM_001127198.5(TMC6):c.892-2A>G	Pathogenic
836197	NM_001127198.5(TMC6):c.967del (p.Leu323fs)	Pathogenic
933595	NM_001127198.5(TMC6):c.306C>A (p.Tyr102Ter)	Pathogenic
3583084	NM_001127198.5(TMC6):c.634-3_654del	Likely pathogenic

SpliceAI

4846 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78113635:C:CT	acceptor_gain	1.0000
17:78117263:ACTC:A	donor_loss	1.0000
17:78117264:CTCA:C	donor_loss	1.0000
17:78117265:TCAC:T	donor_loss	1.0000
17:78117266:CA:C	donor_loss	1.0000
17:78117267:A:AC	donor_gain	1.0000
17:78117267:ACA:A	donor_loss	1.0000
17:78117268:C:A	donor_loss	1.0000
17:78117268:C:CA	donor_gain	1.0000
17:78117268:CA:C	donor_gain	1.0000
17:78117268:CATTG:C	donor_gain	1.0000
17:78117800:A:AC	donor_gain	1.0000
17:78117801:C:CC	donor_gain	1.0000
17:78118967:TCAC:T	donor_loss	1.0000
17:78118970:C:CA	donor_loss	1.0000
17:78118970:CCTT:C	donor_gain	1.0000
17:78119414:CGT:C	acceptor_gain	1.0000
17:78119416:T:TC	acceptor_gain	1.0000
17:78122600:CTCA:C	donor_loss	1.0000
17:78122601:TCACC:T	donor_loss	1.0000
17:78122602:CA:C	donor_loss	1.0000
17:78122603:A:AC	donor_gain	1.0000
17:78122603:AC:A	donor_gain	1.0000
17:78122603:ACCT:A	donor_loss	1.0000
17:78122604:C:CC	donor_gain	1.0000
17:78122604:CC:C	donor_gain	1.0000
17:78122604:CCT:C	donor_gain	1.0000
17:78122604:CCTT:C	donor_gain	1.0000
17:78122745:CCATG:C	acceptor_gain	1.0000
17:78122746:CATG:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000026329 (17:78107351 A>C,G), RS1000143217 (17:78118087 G>A), RS1000310484 (17:78115914 C>G,T), RS1000348982 (17:78128182 C>T), RS1000351055 (17:78128184 A>C,G), RS1000422928 (17:78110042 G>C), RS1000513389 (17:78118295 G>C), RS1000650702 (17:78107537 G>A), RS1000656292 (17:78128407 G>A), RS1000735000 (17:78118685 G>C), RS1000892990 (17:78127282 G>C), RS1000911338 (17:78123050 G>A), RS1001121219 (17:78114968 A>G), RS1001123485 (17:78110438 C>T), RS1001259870 (17:78127529 G>A)

Disease associations

OMIM: gene MIM:605828 | disease phenotypes: MIM:226400, MIM:618231

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermodysplasia verruciformis, susceptibility to, 1	Definitive	Autosomal recessive
epidermodysplasia verruciformis	Strong	Autosomal recessive

Mondo (3): epidermodysplasia verruciformis (MONDO:0009176), epidermodysplasia verruciformis, susceptibility to, 1 (MONDO:0100045), epidermodysplasia verruciformis, susceptibility to, 2 (MONDO:0032614)

Orphanet (1): Inherited epidermodysplasia verruciformis (Orphanet:302)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001051	Seborrheic dermatitis
HP:0001053	Hypopigmented skin patches
HP:0001581	Recurrent skin infections
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002671	Basal cell carcinoma
HP:0002715	Abnormality of the immune system
HP:0002860	Squamous cell carcinoma
HP:0007565	Multiple cafe-au-lait spots
HP:0100585	Telangiectasia of the skin
HP:0200034	Papule
HP:0200035	Skin plaque
HP:0200039	Pustule
HP:0200043	Verrucae

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST004601_177	Red blood cell count	2.000000e-16
GCST004602_299	Mean corpuscular volume	1.000000e-19
GCST004607_80	Plateletcrit	2.000000e-12
GCST004611_132	High light scatter reticulocyte count	1.000000e-11
GCST004611_133	High light scatter reticulocyte count	6.000000e-17
GCST004612_80	High light scatter reticulocyte percentage of red cells	7.000000e-14
GCST004612_81	High light scatter reticulocyte percentage of red cells	9.000000e-22
GCST004619_116	Reticulocyte fraction of red cells	8.000000e-13
GCST004619_140	Reticulocyte fraction of red cells	1.000000e-20
GCST004621_197	Red cell distribution width	3.000000e-19
GCST004622_60	Reticulocyte count	1.000000e-13
GCST004628_23	Immature fraction of reticulocytes	4.000000e-16
GCST004630_221	Mean corpuscular hemoglobin	2.000000e-12
GCST004939_2	Glycated hemoglobin levels	5.000000e-09
GCST005145_3	Glycated hemoglobin levels	5.000000e-20
GCST005557_3	Serum uric acid levels	1.000000e-06
GCST005993_17	Mean corpuscular hemoglobin	7.000000e-12
GCST005996_5	Red blood cell count	4.000000e-15
GCST006001_4	Hemoglobin A1c levels	7.000000e-14
GCST006011_55	Mean corpuscular volume	6.000000e-14
GCST006804_64	Red cell distribution width	2.000000e-12
GCST008398_15	Glycated hemoglobin levels	1.000000e-16
GCST010083_236	Hemoglobin levels	3.000000e-13
GCST012133_2	hemolysis of donated blood (cold-storage)	1.000000e-08
GCST90002383_79	Hematocrit	2.000000e-11
GCST90002384_425	Hemoglobin	7.000000e-15
GCST90002385_325	High light scatter reticulocyte count	2.000000e-14
GCST90002385_326	High light scatter reticulocyte count	2.000000e-16
GCST90002386_199	High light scatter reticulocyte percentage of red cells	2.000000e-17
GCST90002386_200	High light scatter reticulocyte percentage of red cells	1.000000e-23

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004541	HbA1c measurement
EFO:0004761	uric acid measurement
EFO:0004509	hemoglobin measurement
EFO:0009473	hemolysis
EFO:0004348	hematocrit
EFO:0010701	mean reticulocyte volume
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004819	Epidermodysplasia Verruciformis	C01.925.256.650.810.345; C01.925.825.810.260; C01.925.928.914.345; C17.800.838.790.810.260

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	3
Tretinoin	increases expression	3
Valproic Acid	increases expression, increases methylation	3
Aflatoxin B1	increases expression, increases methylation	3
(+)-JQ1 compound	decreases expression	2
Calcitriol	increases expression, affects cotreatment	2
Nickel	increases expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
propionaldehyde	increases expression	1
bisphenol A	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2LY	HAP1 TMC6 (-) 1	Cancer cell line	Male
CVCL_E2LZ	HAP1 TMC6 (-) 2	Cancer cell line	Male
CVCL_E2M0	HAP1 TMC6 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00973856	Not specified	COMPLETED	Evaluation of the Effectiveness of an Alcohol Based Hand Gel for the Reduction of Warts on the Hands