NAE1

NEDD8 activating enzyme E1 subunit 1, the group of Ubiquitin like modifier activating enzymes

Basic information

Region (hg38): 16:66802875-66873256

Previous symbols: [ "APPBP1" ]

Links

ENSG00000159593 ∙ NCBI:8883 ∙ OMIM:603385 ∙ HGNC:621 ∙ Uniprot:Q13564 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (Limited), mode of inheritance: AR
• neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia	AR	General	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	Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic	36608681

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NAE1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NAE1 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				1		1
missense			26			26
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	26	1	0

Variants in NAE1

This is a list of pathogenic ClinVar variants found in the NAE1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-66803065-T-G		not specified	Uncertain significance (Mar 12, 2024)
16-66803085-G-C		not specified	Uncertain significance (Jun 11, 2021)
16-66805818-T-C		Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia	Uncertain significance (Mar 29, 2024)
16-66805825-A-T		not specified	Uncertain significance (Apr 26, 2023)
16-66805996-A-G		not specified	Uncertain significance (Oct 12, 2021)
16-66808562-C-T		Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia	Pathogenic (Jan 27, 2023)
16-66809049-C-A		not specified	Uncertain significance (Sep 30, 2021)
16-66810410-G-A		not specified	Uncertain significance (Sep 01, 2021)
16-66810413-C-T		not specified	Uncertain significance (Jun 08, 2022)
16-66810741-C-T		not specified	Uncertain significance (Dec 14, 2023)
16-66813625-C-T		not specified	Uncertain significance (Oct 16, 2023)
16-66813805-G-C		Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia	Pathogenic (-)
16-66813810-G-A		not specified	Uncertain significance (Apr 07, 2022)
16-66813818-T-G		not specified	Uncertain significance (Aug 02, 2021)
16-66816612-T-C		not specified	Uncertain significance (Jul 27, 2022)
16-66817004-A-C		not specified	Uncertain significance (Jun 16, 2023)
16-66817477-T-C		not specified	Uncertain significance (Nov 10, 2022)
16-66818537-C-T		not specified	Uncertain significance (Dec 15, 2023)
16-66818538-A-G		not specified	Uncertain significance (Oct 20, 2021)
16-66818589-T-C		not specified	Uncertain significance (May 20, 2024)
16-66818619-T-C		not specified	Uncertain significance (May 24, 2023)
16-66821477-T-C		not specified	Uncertain significance (Sep 01, 2021)
16-66823234-G-C		not specified	Uncertain significance (Feb 15, 2023)
16-66823268-G-C		not specified	Uncertain significance (Mar 22, 2023)
16-66823284-T-C		not specified	Uncertain significance (May 07, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NAE1	protein_coding	protein_coding	ENST00000290810	20	70382

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.80e-13	0.800	125697	0	51	125748	0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.09	218	268	0.813	0.0000130	3498
Missense in Polyphen		35	76.376	0.45826		995
Synonymous	1.04	79	91.6	0.862	0.00000456	946
Loss of Function	1.85	26	38.3	0.678	0.00000216	454

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000348	0.000348
Ashkenazi Jewish	0.00104	0.000993
East Asian	0.0000544	0.0000544
Finnish	0.0000471	0.0000462
European (Non-Finnish)	0.000152	0.000149
Middle Eastern	0.0000544	0.0000544
South Asian	0.000287	0.000261
Other	0.00103	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. {ECO:0000269|PubMed:10207026, ECO:0000269|PubMed:10722740, ECO:0000269|PubMed:12740388}.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Alzheimers Disease;Post-translational protein modification;Metabolism of proteins;Neddylation (Consensus)

Recessive Scores

• pRec: 0.149

Intolerance Scores

• loftool: 0.931
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.6

Haploinsufficiency Scores

• pHI: 0.660
• hipred: Y
• hipred_score: 0.690
• ghis: 0.674

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.854

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nae1
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype

Gene ontology

• Biological process: signal transduction;protein modification by small protein conjugation;mitotic DNA replication checkpoint;regulation of apoptotic process;regulation of neuron apoptotic process;post-translational protein modification;protein neddylation;neuron apoptotic process
• Cellular component: cytoplasm;cytosol;plasma membrane
• Molecular function: protein binding;NEDD8 activating enzyme activity;ubiquitin protein ligase binding;protein heterodimerization activity