NLGN4X

neuroligin 4 X-linked, the group of Neuroligins

Basic information

Region (hg38): X:5840636-6228867

Previous symbols: [ "NLGN4" ]

Links

ENSG00000146938 ∙ NCBI:57502 ∙ OMIM:300427 ∙ HGNC:14287 ∙ Uniprot:Q8N0W4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autism, susceptibility to, X-linked 2 (Limited), mode of inheritance: XLR
• autism, susceptibility to, X-linked 2 (Moderate), mode of inheritance: XL
• autism, susceptibility to, X-linked 2 (Strong), mode of inheritance: XL
• autism, susceptibility to, X-linked 2 (Limited), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autism susceptibility, X-linked 2	XL	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	12669065; 14963808; 18231125; 19645625; 19726642

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NLGN4X gene.

• not provided (141 variants)
• Inborn genetic diseases (65 variants)
• not specified (24 variants)
• Autism, susceptibility to, X-linked 2 (10 variants)
• Asperger syndrome, X-linked, susceptibility to, 2;Autism, susceptibility to, X-linked 2 (3 variants)
• NLGN4X-related condition (3 variants)
• Intellectual disability (2 variants)
• Asperger syndrome, X-linked, susceptibility to, 2 (1 variants)
• History of neurodevelopmental disorder (1 variants)
• Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NLGN4X gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	38	7	51
missense	2		104	12	1	119
nonsense	1		4			5
start loss						0
frameshift	1					1
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region			3			3
non coding					11	11
Total	4	2	115	50	19

Variants in NLGN4X

This is a list of pathogenic ClinVar variants found in the NLGN4X region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-5892533-C-T			Benign (Jun 19, 2021)
X-5892643-G-T			Benign (Jun 19, 2021)
X-5892715-C-T			Benign (Jun 19, 2021)
X-5892824-C-G			Uncertain significance (Oct 18, 2019)
X-5892840-C-T		Autism, susceptibility to, X-linked 2	Uncertain significance (Jun 16, 2022)
X-5892852-T-C		NLGN4X-related disorder	Uncertain significance (Oct 31, 2023)
X-5892863-T-C		Inborn genetic diseases	Uncertain significance (Dec 17, 2023)
X-5892878-G-T		Inborn genetic diseases	Uncertain significance (Sep 06, 2022)
X-5892903-T-A			Uncertain significance (Oct 19, 2023)
X-5892907-C-T		not specified	Uncertain significance (Apr 09, 2015)
X-5892908-G-A		not specified • Inborn genetic diseases • Autism, susceptibility to, X-linked 2	Conflicting classifications of pathogenicity (Jul 01, 2023)
X-5892938-T-C		NLGN4X-related disorder	Uncertain significance (Oct 26, 2023)
X-5892943-C-T		Inborn genetic diseases	Likely benign (May 01, 2023)
X-5892944-G-A		Inborn genetic diseases	Uncertain significance (Oct 11, 2017)
X-5892947-A-G			Uncertain significance (May 31, 2022)
X-5892951-G-A			Uncertain significance (May 07, 2023)
X-5892967-C-T		NLGN4X-related disorder	Likely benign (Sep 22, 2020)
X-5892971-C-T			Uncertain significance (Oct 01, 2016)
X-5892973-G-C		NLGN4X-related disorder	Likely benign (May 09, 2022)
X-5892974-C-T		Autism, susceptibility to, X-linked 2	Uncertain significance (Jul 23, 2021)
X-5892980-G-A		Inborn genetic diseases	Uncertain significance (Aug 25, 2018)
X-5892984-G-C		Intellectual disability • Inborn genetic diseases	Uncertain significance (Oct 07, 2019)
X-5892988-G-A		not specified • Inborn genetic diseases • NLGN4X-related disorder	Benign/Likely benign (Apr 19, 2021)
X-5892997-C-T		not specified • Inborn genetic diseases	Benign (Dec 31, 2019)
X-5893009-C-A			Uncertain significance (Aug 23, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NLGN4X	protein_coding	protein_coding	ENST00000381095	5	388227

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.993	0.00733	125744	1	2	125747	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.70	222	368	0.604	0.0000331	5371
Missense in Polyphen		105	213.71	0.49131		3005
Synonymous	-1.51	193	168	1.15	0.0000173	1627
Loss of Function	3.84	1	19.1	0.0524	0.00000137	320

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000378	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Putative neuronal cell surface protein involved in cell- cell-interactions.
• Disease: DISEASE: Asperger syndrome, X-linked, 2 (ASPGX2) [MIM:300497]: A syndrome with features similar to autism. Affected individuals exhibit qualitative impairment in social interaction, as manifest by impairment in the use of non-verbal behaviors such as eye-to- eye gaze, facial expression, body postures, and gestures, failure to develop appropriate peer relationships, and lack of social sharing or reciprocity. Patients also exhibit restricted, repetitive and stereotyped patterns of behavior, interests, and activities, including abnormal preoccupation with certain activities and inflexible adherence to routines or rituals. Asperger syndrome is primarily distinguished from autism by the higher cognitive abilities and a more normal and timely development of language and communicative phrases. {ECO:0000269|PubMed:14963808}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Cell adhesion molecules (CAMs) - Homo sapiens (human);Neuronal System;Neurexins and neuroligins;Protein-protein interactions at synapses (Consensus)

Recessive Scores

• pRec: 0.227

Intolerance Scores

• loftool: 0.149
• rvis_EVS: -0.84
• rvis_percentile_EVS: 11.18

Haploinsufficiency Scores

• pHI: 0.816
• hipred: Y
• hipred_score: 0.507
• ghis: 0.607

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.791

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Gene ontology

• Biological process: brainstem development;neuron cell-cell adhesion;learning;cerebellum development;neuron differentiation;adult behavior;social behavior;organ growth;cell-cell junction organization;synaptic vesicle endocytosis;modulation of chemical synaptic transmission;synapse organization;vocalization behavior;negative regulation of excitatory postsynaptic potential;postsynaptic membrane assembly;presynaptic membrane assembly;presynapse assembly
• Cellular component: plasma membrane;integral component of plasma membrane;cell surface;postsynaptic density;integral component of membrane;cell junction;dendrite;synapse;postsynaptic membrane;excitatory synapse;spanning component of membrane;presynapse;symmetric, GABA-ergic, inhibitory synapse;asymmetric, glutamatergic, excitatory synapse
• Molecular function: protein binding;chloride ion binding;signaling receptor activity;neurexin family protein binding;protein homodimerization activity;cell adhesion molecule binding;scaffold protein binding