NPTX1

protein-coding

neuronal pentraxin 1, the group of Long pentraxins

Gene summary

NPTX1 is a member of the neuronal pentraxin gene family. Neuronal pentraxin 1 is similar to the rat NP1 gene which encodes a binding protein for the snake venom toxin taipoxin. Human NPTX1 mRNA is exclusively localized to the nervous system. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002522.4

Inheritance

ClinVar variants

P:5U:57B:8

Top phenotype

Spinocerebellar ataxia 50

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr17:80,466,834-80,477,843

External References & Databases

Ensembl (ENSG00000171246)

Transcript & Mutation Effects

hg38 • Region Span ~11.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia 50MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859334

Submitter: Ambry Genetics

spinocerebellar ataxia 50STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859334

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0000437

Submitter: PanelApp Australia

autosomal dominant cerebellar ataxiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020380

Submitter: ClinGen

*NPTX1* was first associated with autosomal dominant cerebellar ataxia in 2022 (Coutelier M, et al., PMID: 34788392). The *NPTX1* gene is a member of the neuronal pentraxin family and encodes a long neuronal pentraxin protein. It has various cellular and synaptic functions including mediating the uptake of synaptic material and presynaptic toxins (PMID: 8884281). The reported phenotype is characterized by a slowly progressive gait ataxia, oculomotor apraxia and other eye movement abnormalities, and cerebellar atrophy on brain imaging. Other features may be present as well and onset is typically, but not always, in adulthood (PMID: 20301317). Four missense variants that have been reported in 8 probands across 3 publications (PMIDs: 34788392, 35285082, 35560436) are included in this curation. One variant, c.1165G>A (p.Gly389Arg), was reported in five of the probands, but was excluded as a founder variant after haplotype analysis was performed (PMID: 34788392). The mechanism of pathogenicity is unclear. This gene-disease relationship is supported by expression studies showing that this gene is expressed in the central nervous system, with highest expression in the cerebellum (PMIDs: 34788392, 32913098). In summary, there is presently limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date September 11, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 50AD

Manifestation: 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: 34788392; 35285082; 35288776; 35560436

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPTX1 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 52

not providedTotal: 11

Spinocerebellar ataxia 50Total: 8

NPTX1-related disordersTotal: 1

NPTX1-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002522.4. 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			2 clinvar	2 clinvar	2 clinvar	6
missense	1 clinvar	4 clinvar	54 clinvar	4 clinvar		63
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	1	4	57	6	2	70

Highest pathogenic variant AF is 0.0000037183338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002522.4	RefSeq	NP_002513.2	5	MANE Select
ENST00000306773.5	Ensembl	ENSP00000307549.4	5	MANE Select
ENST00000571100.2	Ensembl	ENSP00000511957.1	3	Standard
ENST00000571100.3	Ensembl	ENSP00000511957.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chemical synaptic transmission
central nervous system development
axonogenesis involved in innervation
regulation of postsynaptic neurotransmitter receptor activity

Molecular Function

metal ion binding

Cellular Component

plasma membrane
transport vesicle
neuron projection
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306773
Coding exons: 5
Length: 10696
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125688
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.87	168	252	0.668	0.0000134	2783
Missense (PolyPhen)		35	86.559	0.40435		931
Synonymous	-0.0986	116	115	1.01	0.00000677	891
Loss of Function	3.03	3	16.1	0.186	6.93e-7	174

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses. {ECO:0000250}.;

Recessive Scores

pRec: 0.185

Intolerance Scores

LoFtool: 0.240
RVIS EVS: -0.29
RVIS percentile EVS: 33.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.838

Gene Damage Prediction

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