NGLY1

N-glycanase 1

Basic information

Region (hg38): 3:25718943-25790039

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 (598 variants)
• not provided (126 variants)
• Inborn genetic diseases (28 variants)
• not specified (19 variants)
• Congenital disorder of deglycosylation 1 (18 variants)
• Neurodevelopmental delay (2 variants)
• Abnormal brain morphology (1 variants)
• Neurodevelopmental abnormality (1 variants)
• NGLY1-related condition (1 variants)
• Peripheral neuropathy;Intellectual disability;Neuromotor delay (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	139	2	145
missense	2	3	260	11		276
nonsense	19	5	1			25
start loss			1			1
frameshift	29	10	3			42
inframe indel			5			5
splice donor/acceptor (+/-2bp)	2	4				6
splice region		1	15	28	2	46
non coding			2	74	32	108
Total	52	22	276	224	34

Highest pathogenic variant AF is 0.0000328

Variants in NGLY1

This is a list of pathogenic ClinVar variants found in the NGLY1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-25719469-A-T			Uncertain significance (Aug 02, 2023)
3-25719471-T-C		Congenital disorder of deglycosylation	Uncertain significance (Aug 28, 2021)
3-25719472-G-A		Congenital disorder of deglycosylation	Likely benign (Nov 17, 2023)
3-25719472-GA-CT		Congenital disorder of deglycosylation	Uncertain significance (May 18, 2021)
3-25719475-T-C		Congenital disorder of deglycosylation	Likely benign (Aug 29, 2022)
3-25719480-T-A		Congenital disorder of deglycosylation	Uncertain significance (Jul 05, 2022)
3-25719484-T-A		Congenital disorder of deglycosylation	Likely benign (Aug 14, 2019)
3-25719484-T-G		Congenital disorder of deglycosylation	Likely benign (Sep 11, 2023)
3-25719492-A-G		Congenital disorder of deglycosylation	Likely benign (Dec 02, 2021)
3-25719494-C-T		Congenital disorder of deglycosylation 1	Uncertain significance (Mar 02, 2021)
3-25719502-T-C		Congenital disorder of deglycosylation	Likely benign (Aug 30, 2023)
3-25719505-A-G		Congenital disorder of deglycosylation	Likely benign (Jul 31, 2023)
3-25719507-G-A		Congenital disorder of deglycosylation	Conflicting classifications of pathogenicity (Aug 11, 2022)
3-25719508-G-A		Congenital disorder of deglycosylation	Likely benign (Aug 19, 2023)
3-25719511-AT-A			Likely pathogenic (Oct 18, 2017)
3-25719512-T-C		Congenital disorder of deglycosylation • Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
3-25719514-TA-T		Congenital disorder of deglycosylation	Likely pathogenic (Mar 21, 2019)
3-25719524-C-G		Congenital disorder of deglycosylation	Uncertain significance (Sep 01, 2021)
3-25719531-G-C		Congenital disorder of deglycosylation	Uncertain significance (Dec 07, 2023)
3-25719533-TG-T		Congenital disorder of deglycosylation • Congenital disorder of deglycosylation 1	Pathogenic (Jan 11, 2024)
3-25719536-G-T		Congenital disorder of deglycosylation • Inborn genetic diseases	Uncertain significance (Nov 22, 2023)
3-25719538-G-A		Congenital disorder of deglycosylation	Likely benign (Feb 01, 2020)
3-25719542-TG-T		Congenital disorder of deglycosylation	Pathogenic (Jul 08, 2022)
3-25719544-C-T			Likely pathogenic (Oct 23, 2020)
3-25719549-C-T		Congenital disorder of deglycosylation	Uncertain significance (Jul 12, 2022)

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