NAGPA

protein-coding

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase

Gene summary

Hydrolases are transported to lysosomes after binding to mannose 6-phosphate receptors in the trans-Golgi network. This gene encodes the enzyme that catalyzes the second step in the formation of the mannose 6-phosphate recognition marker on lysosomal hydrolases. Commonly known as 'uncovering enzyme' or UCE, this enzyme removes N-acetyl-D-glucosamine (GlcNAc) residues from GlcNAc-alpha-P-mannose moieties and thereby produces the recognition marker. The encoded preproprotein is proteolytically processed by furin to generate the mature enzyme, a homotetramer of two disulfide-linked homodimers. Mutations in this gene are associated with developmental stuttering in human patients. [provided by RefSeq, Oct 2015]

MANE transcript

NM_016256.4

Inheritance

—

ClinVar variants

U:120B:23

Top phenotype

NAGPA-related disorder

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr16:5,024,844-5,034,141

External References & Databases

Ensembl (ENSG00000103174)

Transcript & Mutation Effects

hg38 • Region Span ~9.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NAGPA variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 105

not providedTotal: 11

NAGPA-related disorderTotal: 11

Stuttering, familial persistent, 2Total: 2

Variant of unknown significanceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016256.4. 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			3 clinvar	11 clinvar	2 clinvar	16
missense			108 clinvar	8 clinvar	2 clinvar	118
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	120	19	4	143

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016256.4	RefSeq	NP_057340.2	10	MANE Select
ENST00000312251.8	Ensembl	ENSP00000310998.3	10	MANE Select
ENST00000381955.7	Ensembl	ENSP00000371381.3	9	Standard
ENST00000381955.8	Ensembl	ENSP00000371381.3	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)

Biological Process

carbohydrate metabolic process
cellular protein modification process
protein glycosylation
protein targeting to lysosome
lysosome organization

Molecular Function

N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase activity
protein binding

Cellular Component

integral component of membrane
Golgi cisterna membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000312251
Coding exons: 10
Length: 9298
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.37	377	309	1.22	0.0000181	3268
Missense (PolyPhen)		107	103.23	1.0365		1060
Synonymous	-3.61	193	139	1.39	0.00000915	1059
Loss of Function	0.434	19	21.2	0.898	9.32e-7	227

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000095	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00058	0.00054	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the second step in the formation of the mannose 6-phosphate targeting signal on lysosomal enzyme oligosaccharides by removing GlcNAc residues from GlcNAc-alpha-P- mannose moieties, which are formed in the first step. Also hydrolyzes UDP-GlcNAc, a sugar donor for Golgi N- acetylglucosaminyltransferases. {ECO:0000269|PubMed:23572527}.;
Disease: DISEASE: Note=Defects in NAGPA have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech. {ECO:0000269|PubMed:20147709}.;

Recessive Scores

pRec: 0.274

Intolerance Scores

LoFtool: 0.575
RVIS EVS: 0
RVIS percentile EVS: 54.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.941

Gene Damage Prediction

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