NEXMIF

Chr XXLD

neurite extension and migration factor

Also known as: KIAA2022, KIDLIA, MRX98, XLID98, XPN

NCBI Gene: 340533 ENSG00000050030 UniProt: Q5QGS0 OMIM: 300524

The NEXMIF protein localizes to the nucleus and mutations cause X-linked intellectual developmental disorder (XLID-98) with an X-linked dominant inheritance pattern. Mutations predominantly cause disease through loss-of-function mechanisms, with the gene showing high intolerance to loss-of-function variants (pLI 0.999, LOEUF 0.198), indicating haploinsufficiency is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLDLOEUF 0.201 OMIM phenotype

Clinical Summary— NEXMIF

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

214 unique Pathogenic / Likely Pathogenic· 606 VUS of 1326 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 4.90

OE 0.06 (0.03–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.27Z-score

OE missense 0.85 (0.78–0.92)

464 obs / 547.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.20)

0≤0.351.4

Missense OE?0.85 (0.78–0.92)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 2 / 31.9Missense obs/exp: 464 / 547.8Syn Z: -0.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNEXMIF-related intellectual disability and epilepsy (heterozygous)LOFmonoallelic_X_heterozygous

strongNEXMIF-related intellectual disability and epilepsy (hemizygous)OTHERXLR

This gene — mechanism propensity

0.2698th %ile

GOF

0.3392th %ile

LOF

0.87top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 98% of P/LP variants are LoF · LOEUF 0.20 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

1326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic183

Likely Pathogenic31

VUS606

Likely Benign305

Benign50

Conflicting63

183

Pathogenic

Likely Pathogenic

606

VUS

305

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	182	0	1	0	183
Likely Pathogenic	27	1	3	0	31
VUS	4	593	6	3	606
Likely Benign	1	71	15	218	305
Benign	0	32	1	17	50
Conflicting	—				63
Total	214	697	26	238	1,238

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

64 pathogenic / likely-pathogenic (of 74) ClinVar copy-number / structural variants overlap NEXMIF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →