NGLY1

N-glycanase 1

Basic information

Region (hg38): 3:25718944-25790039

Links

ENSG00000151092

∙ NCBI:55768 ∙ OMIM:610661 ∙ HGNC:17646 ∙ Uniprot:Q96IV0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

congenital disorder of deglycosylation 1 (Definitive), mode of inheritance: AR
NGLY1-deficiency (Strong), mode of inheritance: AR
congenital disorder of deglycosylation 1 (Strong), mode of inheritance: AR
NGLY1-deficiency (Supportive), mode of inheritance: AR
congenital disorder of deglycosylation 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital disorder of deglycosylation	AR	Hematologic	Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery	Biochemical; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic	22581936; 24651605
Hepatic-metabolized agents should be avoided

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NGLY1 gene.

Congenital_disorder_of_deglycosylation (761 variants)
not_provided (128 variants)
Inborn_genetic_diseases (78 variants)
Congenital_disorder_of_deglycosylation_1 (48 variants)
not_specified (20 variants)
NGLY1-related_disorder (14 variants)
Intellectual_disability (3 variants)
Neurodevelopmental_delay (2 variants)
Peripheral_neuropathy (1 variants)
Lactic_acidosis (1 variants)
Fetal_growth_restriction (1 variants)
Global_developmental_delay (1 variants)
Abnormal_brain_morphology (1 variants)
Neuromotor_delay (1 variants)
Neurodevelopmental_abnormality (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NGLY1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000018297.4. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	5 clinvar	212 clinvar	2 clinvar	220
missense	5 clinvar	8 clinvar	290 clinvar	19 clinvar		322
nonsense	31 clinvar	9 clinvar				40
start loss		3	1			4
frameshift	34 clinvar	21 clinvar	3 clinvar			58
splice donor/acceptor (+/-2bp)	5 clinvar	8 clinvar	1 clinvar			14
Total	75	50	300	231	2

Highest pathogenic variant AF is 0.000399048

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NGLY1	protein_coding	protein_coding	ENST00000280700	12	71096

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.51e-13	0.767	125636	0	112	125748	0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0726	336	332	1.01	0.0000163	4246
Missense in Polyphen		86	105.01	0.81893		1262
Synonymous	0.380	116	121	0.956	0.00000584	1223
Loss of Function	1.80	26	38.0	0.685	0.00000215	438

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000395	0.000395
Ashkenazi Jewish	0.00	0.00
East Asian	0.000831	0.000816
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000636	0.000624
Middle Eastern	0.000831	0.000816
South Asian	0.000364	0.000359
Other	0.000819	0.000815

dbNSFP

Source: dbNSFP

Function: FUNCTION: Specifically deglycosylates the denatured form of N- linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl- glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high- mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins. {ECO:0000269|PubMed:14749736, ECO:0000269|PubMed:15358861}.;
Disease: DISEASE: Congenital disorder of deglycosylation (CDDG) [MIM:615273]: A multisystem disorder characterized by developmental delay, hypotonia, abnormal involuntary movements and alacrima or poor tear production. Other features include microcephaly, intractable seizures, abnormal eye movements and evidence of liver dysfunction, probably due to cytoplasmic accumulation of storage material in vacuoles. {ECO:0000269|PubMed:22581936, ECO:0000269|PubMed:24651605}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);Post-translational protein modification;Metabolism of proteins;Asparagine N-linked glycosylation;N-glycan trimming in the ER and Calnexin/Calreticulin cycle (Consensus)

Recessive Scores

pRec: 0.557

Intolerance Scores

loftool: 0.588
rvis_EVS: -0.55
rvis_percentile_EVS: 19.8

Haploinsufficiency Scores

pHI: 0.512
hipred: N
hipred_score: 0.486
ghis: 0.577

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: S
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.283

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Ngly1
Phenotype: cellular phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);

Gene ontology

Biological process: protein folding;protein quality control for misfolded or incompletely synthesized proteins;glycoprotein catabolic process;protein deglycosylation
Cellular component: nucleus;cytoplasm;cytosol
Molecular function: peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity;protein binding;metal ion binding