ALG14

protein-coding

ALG14 UDP-N-acetylglucosaminyltransferase subunit, the group of UDP-N-acetylglucosaminyltransferase subunits

Gene summary

This gene is a member of the glycosyltransferase 1 family. The encoded protein and ALG13 are thought to be subunits of UDP-GlcNAc transferase, which catalyzes the first two committed steps in endoplasmic reticulum N-linked glycosylation. Mutations in this gene have been linked to congenital myasthenic syndrome (CMSWTA). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

MANE transcript

NM_144988.4

Inheritance

ClinVar variants

P:5U:87B:44

Top phenotype

Myasthenic syndrome, congenital 15

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr1:94,974,405-95,072,951

External References & Databases

Ensembl (ENSG00000172339)

Transcript & Mutation Effects

hg38 • Region Span ~98.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myasthenic syndromes with glycosylation defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018144

Submitter: Orphanet

congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: PanelApp Australia

myopathy, epilepsy, and progressive cerebral atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033619

Submitter: Labcorp Genetics (formerly Invitae)

congenital disorder of glycosylationLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015286

Submitter: ClinGen

***ALG14*** was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Cossins J, et al., 2013 (PMID: 23404334). At least 14 unique variants (mostly missense and one intronic variant) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 7 probands from publications (PMIDs:23404334, 28733338, 30221345, 33751823, 34971077 ). Patients may exhibit a range of neurological abnormalities, intellectual disabilities, epilepsy, and dysmorphic features, or they may have a neuromuscular transmission disorder associated with muscle weakness and fatigue. No supporting segregation information is available. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of ***ALG14***, which encodes a subunit of the UDP-N-acetylglucosamine transferase enzyme responsible for adding the second N-acetylglucosamine residue during the synthesis of the lipid-linked oligosaccharide (LLO) in the endoplasmic reticulum (ER) (PMID:28733338, 16100110). Co-immunoprecipitation (coIP) confirms that ***Alg13*** and ***Alg14*** form a hetero-oligomeric complex on the cytosolic face of the ER to catalyze the transfer of UDP-GlcNAc onto the growing oligosaccharide chain during core oligosaccharide synthesis on the ER (PMID:16100110). In summary, there is 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. A classification of **LIMITED** was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 2/21/24 (SOP Version 10).

congenital myasthenic syndrome 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014542

Submitter: Labcorp Genetics (formerly Invitae)

congenital myasthenic syndrome 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014542

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital 15AR

Manifestation: Musculoskeletal; Neurologic

Intervention: Musculoskeletal; Neurologic

Rationale: Individuals have been described as manifesting with progressive weakness, and have been reported who have demonstrated long-term benefit from medical treatment (with anticholinesterase medication)

Refs: 23404334

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG14 variants in ClinVar

9 Conditions Cataloged

Congenital myasthenic syndrome 15Total: 130

Inborn genetic diseasesTotal: 40

not providedTotal: 33

Myopathy, epilepsy, and progressive cerebral atrophyTotal: 22

Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse faciesTotal: 18

ALG14-related disorderTotal: 11

not specifiedTotal: 5

Congenital myopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144988.4. 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				35 clinvar	2 clinvar	37
missense	2 clinvar	1 clinvar	81 clinvar	7 clinvar		91
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	2	3	87	42	2	136

Highest pathogenic variant AF is 0.00022866619

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144988.4	RefSeq	NP_659425.1	4	MANE Select
ENST00000370205.6	Ensembl	ENSP00000359224.4	4	MANE Select
NM_001305242.2	RefSeq	NP_001292171.1	5	Standard
ENST00000897799.1	Ensembl	ENSP00000567858.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

N-Glycan biosynthesis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
Asparagine N-linked glycosylation

Biological Process

dolichol-linked oligosaccharide biosynthetic process

Molecular Function

N-acetylglucosaminyldiphosphodolichol N-acetylglucosaminyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
nuclear membrane
UDP-N-acetylglucosamine transferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370205
Coding exons: 4
Length: 98539
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125745
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.266	118	126	0.933	0.00000661	1376
Missense (PolyPhen)		36	46.126	0.78048		493
Synonymous	0.552	45	50.0	0.901	0.00000280	461
Loss of Function	1.15	6	9.90	0.606	5.71e-7	100

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in protein N-glycosylation. May play a role in the second step of the dolichol-linked oligosaccharide pathway. May anchor the catalytic subunit ALG13 to the ER. {ECO:0000269|PubMed:16100110}.;
Disease: DISEASE: Myasthenic syndrome, congenital, 15 (CMS15) [MIM:616227]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. {ECO:0000269|PubMed:23404334}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.410
RVIS EVS: 0.19
RVIS percentile EVS: 66.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.255

Gene Damage Prediction

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