B4GALNT1

protein-coding

beta-1,4-N-acetyl-galactosaminyltransferase 1, the group of Beta 4-glycosyltransferases

Gene summary

GM2 and GD2 gangliosides are sialic acid-containing glycosphingolipids. GalNAc-T is the enzyme involved in the biosynthesis of G(M2) and G(D2) glycosphingolipids. GalNAc-T catalyzes the transfer of GalNAc into G(M3) and G(D3) by a beta-1,4 linkage, resulting in the synthesis of G(M2) and G(D2), respectively. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

Previous symbols:

GALGT
SPG26

MANE transcript

NM_001478.5

Inheritance

ClinVar variants

P:42U:184B:99

Top phenotype

Spastic paraplegia 26, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr12:57,623,409-57,633,239

External References & Databases

Ensembl (ENSG00000135454)

Transcript & Mutation Effects

hg38 • Region Span ~9.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012213

Submitter: Labcorp Genetics (formerly Invitae)

complex hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*B4GALNT1* gene was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2005 (Wilkinson et al., PMID: 15635080). Unlike the autosomal dominant form of B4GALNT1-related HSP, the autosomal recessive form shows a broad phenotypic spectrum within and between families observed in the recorded subjects. Phenotypes reported with *B4GALNT*-related AR HSP include lower limb spasticity and weakness, mild to moderate intellectual impairment, amyotrophy, gait disturbance, and Babinski signs. Therefore, AR variants in *B4GALNT* have been lumped into one disease entity, complex hereditary spastic paraplegia. Fourteen different biallelic, loss-of-function variants (missense, nonsense, frameshift, deletion, duplication, splice-site) that have been reported in 13 families in 6 different publications (PMIDs: 15635080, 24103911, 24283893, 23746551, 30521973, 35775650) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Haploinsufficiency is known to be the mechanism of disease (PMID: 35775650).This gene-disease relationship is not currently supported by experimental evidence. In summary, there is definitive evidence supporting the relationship between *B4GALNT1* and autosomal recessive complex hereditary spastic paraplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on June 1, 2023 (SOP 9).

hereditary spastic paraplegia 26MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012213

Submitter: Ambry Genetics

hereditary spastic paraplegia 26SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012213

Submitter: Orphanet

hereditary spastic paraplegia 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012213

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spastic paraplegia 26, autosomal recessiveAR

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 23746551

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to B4GALNT1 variants in ClinVar

10 Conditions Cataloged

Spastic paraplegiaTotal: 259

not providedTotal: 90

Inborn genetic diseasesTotal: 85

Hereditary spastic paraplegia 26Total: 26

not specifiedTotal: 20

B4GALNT1-related disorderTotal: 13

B4GALNT1-related disordersTotal: 2

AutismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001478.5. 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			4 clinvar	88 clinvar	3 clinvar	95
missense	1 clinvar	6 clinvar	179 clinvar	7 clinvar	1 clinvar	194
nonsense	8 clinvar	1 clinvar	1 clinvar			10
start loss						0
frameshift	12 clinvar	5 clinvar				17
splice donor/acceptor (+/-2bp)	1 clinvar	8 clinvar				9
Total	22	20	184	95	4	325

Highest pathogenic variant AF is 0.00012479108

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001478.5	RefSeq	NP_001469.1	10	MANE Select
ENST00000341156.9	Ensembl	ENSP00000341562.4	10	MANE Select
NM_001276468.2	RefSeq	NP_001263397.1	9	Standard
NM_001276469.2	RefSeq	NP_001263398.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosphingolipid biosynthesis - ganglio series - Homo sapiens (human)
Ganglio Sphingolipid Metabolism
Metabolism of Spingolipids in ER and Golgi apparatus
Metabolism of lipids
Glycosphingolipid biosynthesis - ganglioseries

Biological Process

ganglioside biosynthetic process
carbohydrate metabolic process
glycosphingolipid metabolic process
spermatogenesis
lipid storage

Molecular Function

(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase activity

Cellular Component

Golgi membrane
plasma membrane
membrane
integral component of Golgi membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341156
Coding exons: 10
Length: 9946
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.924	267	313	0.853	0.0000194	3350
Missense (PolyPhen)		72	109.76	0.65597		1069
Synonymous	0.154	133	135	0.983	0.00000838	1173
Loss of Function	2.31	11	23.0	0.479	0.00000113	236

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the biosynthesis of gangliosides GM2, GD2 and GA2. {ECO:0000269|PubMed:1601877}.;
Disease: DISEASE: Spastic paraplegia 26, autosomal recessive (SPG26) [MIM:609195]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG26 is a complicated form characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive. {ECO:0000269|PubMed:23746551}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.489
RVIS EVS: 0.26
RVIS percentile EVS: 70.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.336

Gene Damage Prediction

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