VAPB

VAMP associated protein B and C

Basic information

Region (hg38): 20:58389228-58451101

Links

ENSG00000124164 ∙ NCBI:9217 ∙ OMIM:605704 ∙ HGNC:12649 ∙ Uniprot:O95292 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis type 8 (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• adult-onset proximal spinal muscular atrophy, autosomal dominant (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis type 8 (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis type 8 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 8; Spinal muscular atrophy, late-onset, Finkel type	AD	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	Neurologic	15372378; 18322265; 20940299; 20577002

ClinVar

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

• Amyotrophic lateral sclerosis type 8 (153 variants)
• Adult-onset proximal spinal muscular atrophy, autosomal dominant (152 variants)
• Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant (78 variants)
• Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8 (53 variants)
• not provided (42 variants)
• Inborn genetic diseases (37 variants)
• Amyotrophic Lateral Sclerosis, Dominant (20 variants)
• Spinal Muscular Atrophy, Dominant (20 variants)
• not specified (6 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VAPB 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				23	3	26
missense	1		82	6		89
nonsense			1			1
start loss						0
frameshift			3			3
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	2		4
non coding			94	49	48	191
Total	1	0	180	78	51

Variants in VAPB

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

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

Position	Type	Phenotype	Significance	ClinVar
20-58389257-G-GCCTCGC		Amyotrophic Lateral Sclerosis, Dominant • Spinal Muscular Atrophy, Dominant	Uncertain significance (Jun 14, 2016)
20-58389271-C-T		Adult-onset proximal spinal muscular atrophy, autosomal dominant • Amyotrophic lateral sclerosis type 8	Uncertain significance (Jan 13, 2018)
20-58389294-G-A		Adult-onset proximal spinal muscular atrophy, autosomal dominant • Amyotrophic lateral sclerosis type 8	Uncertain significance (Jan 15, 2018)
20-58389301-G-GC		Amyotrophic Lateral Sclerosis, Dominant • Spinal Muscular Atrophy, Dominant	Uncertain significance (Jun 14, 2016)
20-58389301-G-GCC		Amyotrophic Lateral Sclerosis, Dominant • Spinal Muscular Atrophy, Dominant	Uncertain significance (Jun 14, 2016)
20-58389302-AC-A			Likely benign (Apr 24, 2019)
20-58389302-A-AC		Spinal Muscular Atrophy, Dominant • Amyotrophic Lateral Sclerosis, Dominant	Benign/Likely benign (Dec 29, 2019)
20-58389302-A-ACC			Benign (Oct 07, 2019)
20-58389308-C-A		Amyotrophic lateral sclerosis type 8 • Adult-onset proximal spinal muscular atrophy, autosomal dominant	Uncertain significance (Jan 12, 2018)
20-58389310-C-G		Adult-onset proximal spinal muscular atrophy, autosomal dominant • Amyotrophic lateral sclerosis type 8	Likely benign (Jan 12, 2018)
20-58389323-C-T		Amyotrophic lateral sclerosis type 8 • Adult-onset proximal spinal muscular atrophy, autosomal dominant	Likely benign (Jan 12, 2018)
20-58389427-C-G		Amyotrophic lateral sclerosis type 8 • Adult-onset proximal spinal muscular atrophy, autosomal dominant • Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant	Benign/Likely benign (Nov 01, 2022)
20-58389448-C-T		Amyotrophic lateral sclerosis type 8 • Adult-onset proximal spinal muscular atrophy, autosomal dominant	Uncertain significance (Jan 13, 2018)
20-58389472-G-A		Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8	Uncertain significance (Mar 13, 2022)
20-58389473-A-G		Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8	Uncertain significance (Apr 24, 2019)
20-58389475-C-G		Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8	Uncertain significance (Apr 12, 2023)
20-58389476-A-G		Inborn genetic diseases	Uncertain significance (Jan 31, 2024)
20-58389480-C-G		Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant	Likely benign (May 18, 2021)
20-58389483-G-A		Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8	Likely benign (Jan 22, 2024)
20-58389489-C-T		Amyotrophic lateral sclerosis type 8 • Adult-onset proximal spinal muscular atrophy, autosomal dominant • Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant • Inborn genetic diseases	Conflicting classifications of pathogenicity (May 30, 2021)
20-58389490-G-C		Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant	Uncertain significance (Mar 15, 2022)
20-58389493-C-T		Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis type 8	Uncertain significance (Jul 07, 2019)
20-58389494-C-T		Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant	Uncertain significance (Jun 01, 2021)
20-58389497-A-C		Amyotrophic lateral sclerosis type 8;Adult-onset proximal spinal muscular atrophy, autosomal dominant	Uncertain significance (May 22, 2023)
20-58389502-G-A		Inborn genetic diseases	Uncertain significance (Mar 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VAPB	protein_coding	protein_coding	ENST00000475243	6	61980

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.581	0.417	125744	0	4	125748	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.25	94	135	0.696	0.00000727	1598
Missense in Polyphen		23	52.86	0.43511		615
Synonymous	0.681	44	50.1	0.878	0.00000282	459
Loss of Function	2.56	2	11.3	0.178	5.63e-7	141

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation. {ECO:0000269|PubMed:16891305, ECO:0000269|PubMed:20940299, ECO:0000269|PubMed:22131369}.
• Disease: DISEASE: Spinal muscular atrophy, proximal, adult, autosomal dominant (SMAPAD) [MIM:182980]: A form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAPAD is characterized by proximal muscle weakness that begins in the lower limbs and then progresses to upper limbs, onset in late adulthood (after third decade) and a benign course. Most of the patients remain ambulatory 10 to 40 years after clinical onset. {ECO:0000269|PubMed:15372378}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cholesterol metabolism - Homo sapiens (human);Metabolism of lipids;Metabolism;Sphingolipid de novo biosynthesis;Sphingolipid metabolism (Consensus)

Recessive Scores

• pRec: 0.203

Intolerance Scores

• loftool: 0.282
• rvis_EVS: -0.01
• rvis_percentile_EVS: 53.19

Haploinsufficiency Scores

• pHI: 0.578
• hipred: Y
• hipred_score: 0.710
• ghis: 0.637

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vapb
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype

Zebrafish Information Network

• Gene name: vapb
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: cellular calcium ion homeostasis;endoplasmic reticulum to Golgi vesicle-mediated transport;endoplasmic reticulum organization;modulation by virus of host morphology or physiology;sphingolipid biosynthetic process;endoplasmic reticulum unfolded protein response;IRE1-mediated unfolded protein response;positive regulation of viral genome replication;COPII-coated vesicle budding
• Cellular component: Golgi membrane;cytoplasm;endoplasmic reticulum;endoplasmic reticulum membrane;Golgi apparatus;integral component of membrane;endoplasmic reticulum exit site
• Molecular function: protein binding;microtubule binding;enzyme binding;FFAT motif binding;protein homodimerization activity;cadherin binding;protein heterodimerization activity;beta-tubulin binding