VCX3A

Summary

VCX3A (variable charge X-linked 3A, HGNC:18159) is a protein-coding gene on chromosome Xp22.31, encoding Variable charge X-linked protein 3 (Q9NNX9). May mediate a process in spermatogenesis or may play a role in sex ratio distortion.

This gene belongs to the VCX/Y gene family, which has multiple members on both X and Y chromosomes, and all are expressed exclusively in male germ cells. The X-linked members are clustered on chromosome Xp22 and Y-linked members are two identical copies of the gene within a palindromic region on Yq11. The family members share a high degree of sequence identity, with the exception that a 30-bp unit is tandemly repeated in X-linked members but occurs only once in Y-linked members. The VCX gene cluster is polymorphic in terms of copy number; different individuals may have a different number of VCX genes. VCX/Y genes encode small and highly charged proteins of unknown function. The presence of a putative bipartite nuclear localization signal suggests that VCX/Y members are nuclear proteins. This gene contains 8 repeats of the 30-bp unit.

Source: NCBI Gene 51481 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 7 total — 1 pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity dosage sensitivity unlikely
• MANE Select transcript: NM_016379

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18159
Approved symbol	VCX3A
Name	variable charge X-linked 3A
Location	Xp22.31
Locus type	gene with protein product
Status	Approved
Aliases	VCX-8r, VCX-8R, VCX-A
Ensembl gene	ENSG00000169059
Ensembl biotype	protein_coding
OMIM	300533
Entrez	51481

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000381089, ENST00000398729, ENST00000898738

RefSeq mRNA: 1 — MANE Select: NM_016379 NM_016379

CCDS: CCDS35199

Canonical transcript exons

ENST00000381089 — 3 exons

Exon	Start	End
ENSE00001487459	6533618	6534203
ENSE00001736893	6534396	6534643
ENSE00001804945	6534958	6535118

Expression profiles

Bgee: expression breadth broad, 87 present calls, max score 94.20.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.20	gold quality
right testis	UBERON:0004534	93.99	gold quality
testis	UBERON:0000473	93.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.40	gold quality
apex of heart	UBERON:0002098	53.54	gold quality
lower esophagus mucosa	UBERON:0035834	47.41	silver quality
putamen	UBERON:0001874	45.94	gold quality
skeletal muscle tissue	UBERON:0001134	43.47	gold quality
muscle tissue	UBERON:0002385	41.93	gold quality
right lung	UBERON:0002167	40.82	silver quality
nucleus accumbens	UBERON:0001882	40.70	gold quality
hindlimb stylopod muscle	UBERON:0004252	40.54	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	40.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	39.77	gold quality
caudate nucleus	UBERON:0001873	39.60	gold quality
anterior cingulate cortex	UBERON:0009835	39.52	gold quality
fundus of stomach	UBERON:0001160	39.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	38.62	gold quality
substantia nigra	UBERON:0002038	37.53	gold quality
primary visual cortex	UBERON:0002436	37.39	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	37.35	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
Ammon’s horn	UBERON:0001954	37.16	gold quality
tibial nerve	UBERON:0001323	37.02	gold quality
left uterine tube	UBERON:0001303	36.69	silver quality
brain	UBERON:0000955	36.64	gold quality
cerebral cortex	UBERON:0000956	36.55	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	28.83
E-ANND-3	no	0.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting VCX3A, 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-5696	99.98	72.36	4487
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-3615	95.04	65.37	109

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 40 (dosage sensitivity unlikely). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 3)

• Our data demonstrate that VCX-A can regulate mRNA stability and that it is an example of a tissue-specific decapping regulator. (PMID:17157254)
• two different deletion patterns were observed: the first group included 62 patients with deletion of VCX3A & VCX genes. The second group included 18 patients with breakpoints at several regions on either side of the STS gene not including the VCX3A gene. (PMID:18076704)
• We demonstrate that VCX-A can specifically bind a subset of mRNAs involved in neuritogenesis and is also capable of promoting translational silencing. (PMID:19812318)

Cross-species orthologs

0 orthologs

Paralogs (5): VCY1B (ENSG00000129862), VCY (ENSG00000129864), VCX2 (ENSG00000177504), VCX (ENSG00000182583), VCX3B (ENSG00000205642)

Protein

Protein identifiers

Variable charge X-linked protein 3 — Q9NNX9 (reviewed: Q9NNX9)

Alternative names: Variable charge protein on X with eight repeats, Variably charged protein X-A

All UniProt accessions (2): Q9NNX9, E7ESE9

UniProt curated annotations — full annotation on UniProt →

Function. May mediate a process in spermatogenesis or may play a role in sex ratio distortion.

Tissue specificity. Expressed exclusively in testis.

Similarity. Belongs to the VCX/VCY family.

RefSeq proteins (1): NP_057463* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026653	VCX/VCY1	Family

Pfam: PF15231

UniProt features (18 total): repeat 8, compositionally biased region 6, region of interest 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NNX9-F1	55.46	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 7 (showing top): GOBP_HEAD_DEVELOPMENT, HAMAI_APOPTOSIS_VIA_TRAIL_DN, GOCC_NUCLEOLUS, chrXp22, FOURATI_BLOOD_TWINRIX_AGE_25_83YO_RESPONDERS_VS_POOR_RESPONDERS_0DY_DN, ROZANOV_MMP14_TARGETS_DN, GOBP_CENTRAL_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (1): brain development (GO:0007420)

GO Molecular Function (0):

GO Cellular Component (2): nucleus (GO:0005634), nucleolus (GO:0005730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
central nervous system development	1
animal organ development	1
head development	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VCX3A	DCP2	Q8IU60	855
VCX3A	STS	P08842	776
VCX3A	PRKX	P51817	776
VCX3A	ANOS1	P23352	755
VCX3A	PUDP	Q08623	720
VCX3A	PNPLA4	P41247	700
VCX3A	EDC4	Q6P2E9	676
VCX3A	EDC3	Q96F86	671
VCX3A	SHOX	O15266	622
VCX3A	ARSL	P51690	595
VCX3A	DDX6	P26196	572
VCX3A	XRN1	Q8IZH2	566
VCX3A	ARX	Q96QS3	541
VCX3A	DCP1A	Q9NPI6	496
VCX3A	CD99	P14209	490

IntAct

0 interactions, top by confidence:

BioGRID (1): VCX3A (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1D9BZF0, A6QL64, B4DH59, B5DUH6, D3YZV8, E9Q6E9, O43493, O46383, O77733, P06916, P08116, P0C758, P0DKJ7, P0DKJ8, P0DPF3, P31568, P62521, Q01033, Q01042, Q1HVF7, Q2W8Q7, Q3BBV2, Q42626, Q42627, Q4ZJZ1, Q4ZJZ3, Q5JPF3, Q5MJ10, Q6AXX0, Q6GX35, Q6IC83, Q6P3W6, Q6PGQ1, Q7M4S9, Q7M732, Q86T75, Q8BP27, Q8IZU1, Q8N2N9, Q96QF7

Diamond homologs: O14598, Q9H320, Q9H321, Q9H322, Q9NNX9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	1
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
816240	GRCh37/hg19 Xp22.33-22.31(chrX:1-7810731)x2	Pathogenic

SpliceAI

220 predictions. Top by Δscore:

Variant	Effect	Δscore
X:6534577:C:CT	acceptor_gain	0.9700
X:6534577:C:T	acceptor_gain	0.9700
X:6534204:C:CC	acceptor_gain	0.9400
X:6534578:A:T	acceptor_gain	0.9400
X:6535016:C:A	donor_gain	0.9200
X:6534391:CTCA:C	donor_loss	0.9100
X:6534392:TCA:T	donor_loss	0.9100
X:6534393:CA:C	donor_loss	0.9100
X:6534395:C:CA	donor_loss	0.9100
X:6534748:C:G	acceptor_gain	0.9100
X:6534395:CCTT:C	donor_gain	0.9000
X:6535038:TGCTA:T	donor_gain	0.9000
X:6535041:TA:T	donor_gain	0.9000
X:6534203:TC:T	acceptor_loss	0.8900
X:6534204:CTGG:C	acceptor_loss	0.8900
X:6534205:T:C	acceptor_loss	0.8900
X:6534394:A:AC	donor_gain	0.8900
X:6534395:C:CC	donor_gain	0.8900
X:6534953:CCTA:C	donor_loss	0.8800
X:6534954:CTAC:C	donor_loss	0.8800
X:6534955:TAC:T	donor_loss	0.8800
X:6534956:AC:A	donor_loss	0.8800
X:6534957:C:CG	donor_loss	0.8800
X:6534202:GT:G	acceptor_gain	0.8700
X:6534951:GACCT:G	donor_loss	0.8700
X:6534952:ACCTA:A	donor_loss	0.8700
X:6534200:TAGT:T	acceptor_gain	0.8600
X:6534216:C:CT	acceptor_gain	0.8500
X:6534977:A:AC	donor_gain	0.8500
X:6534978:C:CC	donor_gain	0.8500

AlphaMissense

1227 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:6533931:A:C	S125R	0.721
X:6533931:A:T	S125R	0.721
X:6533933:T:G	S125R	0.721
X:6533871:A:C	S145R	0.720
X:6533871:A:T	S145R	0.720
X:6533873:T:G	S145R	0.720
X:6534129:C:A	M59I	0.720
X:6534129:C:G	M59I	0.720
X:6534129:C:T	M59I	0.720
X:6533901:A:C	S135R	0.718
X:6533901:A:T	S135R	0.718
X:6533903:T:G	S135R	0.718
X:6533841:A:C	S155R	0.715
X:6533841:A:T	S155R	0.715
X:6533843:T:G	S155R	0.715
X:6533991:A:C	S105R	0.688
X:6533991:A:T	S105R	0.688
X:6533993:T:G	S105R	0.688
X:6533811:A:C	S165R	0.683
X:6533811:A:T	S165R	0.683
X:6533813:T:G	S165R	0.683
X:6533961:A:C	S115R	0.677
X:6533961:A:T	S115R	0.677
X:6533963:T:G	S115R	0.677
X:6533862:G:C	S148R	0.641
X:6533862:G:T	S148R	0.641
X:6533864:T:G	S148R	0.641
X:6534150:C:A	K52N	0.612
X:6534150:C:G	K52N	0.612
X:6533922:G:C	S128R	0.594

dbSNP variants (sampled 300 via entrez): RS1000245377 (X:6533274 A>C), RS1002640302 (X:6535417 T>C), RS1008468750 (X:6536400 T>TG), RS1012031060 (X:6536818 C>T), RS1017076136 (X:6535879 G>T), RS1018308519 (X:6536427 C>G), RS1018503831 (X:6536809 C>G), RS1021613549 (X:6536920 G>A,T), RS1026275795 (X:6535935 G>T), RS1032892861 (X:6535058 T>A), RS1034026618 (X:6535428 T>C,G), RS1037064432 (X:6535255 C>G,T), RS1037367125 (X:6536696 A>G), RS1037436560 (X:6534850 G>A,C,T), RS1041997198 (X:6535699 A>G)

Disease associations

OMIM: gene MIM:300533 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1140	Metabolite levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010458	alpha-hydroxybutyric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
cupric oxide	increases expression	1
CGP 52608	affects binding, increases reaction	1
Panobinostat	affects cotreatment, affects expression	1
Acetaminophen	decreases expression	1
Cisplatin	affects expression, affects cotreatment	1
Phenobarbital	affects expression	1
Plant Oils	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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