ALG3

protein-coding

ALG3 alpha-1,3- mannosyltransferase, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases

Gene summary

This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

MANE transcript

NM_005787.6

Inheritance

ClinVar variants

P:42U:113B:57

Top phenotype

Congenital disorder of glycosylation, type Id

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr3:184,242,301-184,249,548

External References & Databases

Ensembl (ENSG00000214160)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG3-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: Labcorp Genetics (formerly Invitae)

ALG3-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: G2P

ALG3-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: PanelApp Australia

ALG3-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: Ambry Genetics

ALG3-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: ClinGen

Variants in *ALG3* were first reported in individuals with an autosomal recessive ALG3-related congenital disorder of glycosylation (CDG) in 2004 (Denecke et al., PMID: 15108280). Phenotypes commonly reported with *ALG3* variants include severe neurological involvement, craniofacial abnormalities, facial dysmorphism, skeletal anomalies, ophthalmologic impairment, and feeding problems. Eight variants (missense, nonsense, frameshift), reported in seven probands, in six publications (PMIDs: 33583022, 34090370, 15108280, 31067009, 32389449, 27172925) are included in this curation. The variant p.Gly55= is recurrent and has been included four times within this curation. Most probands were first identified by a CDG type I N-glycosylation defect as determined by a serum isoelectric focusing assay. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported as loss-of-function. Experimental evidence is inconclusive and has not been curated as “definitive” evidence level has been reached based on genetic evidence alone. In summary, there is definitive evidence to support the relationship between *ALG3* and ALG3-related CDG. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2022 (SOP Version 9).

ALG3-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010998

Submitter: Orphanet

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IdAR

Manifestation: Biochemical; Hematologic; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 8552211; 10581255; 15108280; 15840742; 17551933; 18679822

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG3 variants in ClinVar

7 Conditions Cataloged

ALG3-congenital disorder of glycosylationTotal: 179

not providedTotal: 56

Inborn genetic diseasesTotal: 48

not specifiedTotal: 22

ALG3-related disorderTotal: 11

Congenital disorder of glycosylationTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005787.6. 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		1 clinvar	6 clinvar	51 clinvar	2 clinvar	60
missense	6 clinvar	12 clinvar	104 clinvar	4 clinvar		126
nonsense	5 clinvar	4 clinvar				9
start loss		1 clinvar				1
frameshift	4 clinvar	3 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	2 clinvar			8
Total	17	25	113	55	2	212

Highest pathogenic variant AF is 0.000081193684

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005787.6	RefSeq	NP_005778.1	9	MANE Select
ENST00000397676.8	Ensembl	ENSP00000380793.3	9	MANE Select
NM_001006941.2	RefSeq	NP_001006942.1	9	Standard
ENST00000411922.5	Ensembl	ENSP00000394917.1	2	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
dolichyl-diphosphooligosaccharide biosynthesis
Phosphatidylinositol phosphate metabolism

Biological Process

protein glycosylation
dolichol-linked oligosaccharide biosynthetic process
mannosylation

Molecular Function

alpha-1,3-mannosyltransferase activity
protein binding
dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397676
Coding exons: 9
Length: 7248
Individuals with no LoFs: 124625
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 124676
p: 0.000205

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.317	264	250	1.06	0.0000137	2794
Missense (PolyPhen)		99	106.67	0.92809		1242
Synonymous	-0.793	121	110	1.10	0.00000599	930
Loss of Function	0.891	17	21.5	0.792	0.00000107	213

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00026	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00029	0.00028	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00030	0.00029	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adds the first Dol-P-Man derived mannose in an alpha-1,3 linkage to Man5GlcNAc2-PP-Dol. {ECO:0000269|PubMed:10581255}.;
Disease: DISEASE: Congenital disorder of glycosylation 1D (CDG1D) [MIM:601110]: A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:10581255, ECO:0000269|PubMed:15840742}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.178
RVIS EVS: -0.6
RVIS percentile EVS: 17.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.814

Gene Damage Prediction

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