NEXMIF

protein-coding

neurite extension and migration factor

Gene summary

An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.[provided by RefSeq, Mar 2009]

Previous symbols:

KIAA2022

MANE transcript

NM_001008537.3

Inheritance

ClinVar variants

P:228U:714B:421

Top phenotype

Intellectual developmental disorder, X-linked 98

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chrX:74,732,856-74,925,472

External References & Databases

Ensembl (ENSG00000050030)

Transcript & Mutation Effects

hg38 • Region Span ~192.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*NEXMIF* was first reported in relation to X-linked complex neurodevelopmental disorder in 2013 by Van Maldergem et al. (PMID: 23615299). More than 25 unique variants predicted to cause loss of function of the protein have been described. This gene-disease relationship is also supported by animal models, rescue experiments, and expression studies. In summary, there is definitive evidence supporting the relationship between *NEXMIF* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 5, 2020 (SOP Version 7).

X-linked intellectual disability, Cantagrel typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010483

Submitter: PanelApp Australia

X-linked intellectual disability, Cantagrel typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010483

Submitter: Orphanet

myoclonic-astatic epilepsySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

X-linked intellectual disability, Cantagrel typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010483

Submitter: G2P

X-linked intellectual disability, Cantagrel typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010483

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 98XL

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: 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

Refs: 15466006; 23615299

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEXMIF variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1120

not specifiedTotal: 295

X-linked intellectual disability, Cantagrel typeTotal: 148

NEXMIF-related disorderTotal: 42

Inborn genetic diseasesTotal: 11

Intellectual disabilityTotal: 8

KIAA2022-related disordersTotal: 4

SeizureTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001008537.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			25 clinvar	233 clinvar	14 clinvar	272
missense		1 clinvar	676 clinvar	142 clinvar	30 clinvar	849
nonsense	74 clinvar	12 clinvar	9 clinvar	1 clinvar		96
start loss						0
frameshift	121 clinvar	19 clinvar	2 clinvar	1 clinvar		143
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	195	33	714	377	44	1363

Highest pathogenic variant AF is 0.0000033056895

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001008537.3	RefSeq	NP_001008537.1	3	MANE Select
ENST00000055682.12	Ensembl	ENSP00000055682.5	3	MANE Select
ENST00000616200.2	Ensembl	ENSP00000480284.1	3	Standard
ENST00000616200.3	Ensembl	ENSP00000480284.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of cell-matrix adhesion
negative regulation of cell adhesion mediated by integrin
negative regulation of cell-cell adhesion mediated by cadherin
negative regulation of neuron migration

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000055682
Coding exons: 3
Length: 192599
Individuals with no LoFs: 125687
Homozygous LoFs: 2
Heterozygous LoFs: 5
Defined: 125694
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.27	464	548	0.847	0.0000391	10137
Missense (PolyPhen)		101	185.61	0.54416		3521
Synonymous	-0.387	214	207	1.03	0.0000147	2866
Loss of Function	4.90	2	31.9	0.0627	0.00000251	619

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway. May act by regulating expression of protein-coding genes, such as N-cadherins and integrin beta-1 (ITGB1). {ECO:0000250|UniProtKB:D3ZGX1}.;

Recessive Scores

pRec: 0.0964

Intolerance Scores

RVIS EVS: -0.77
RVIS percentile EVS: 13.1

Essentials

Essential (gene trap): N