VPS41

protein-coding

VPS41 subunit of HOPS complex, the group of Ring finger proteins|HOPS complex

Gene summary

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis. Expression studies in yeast and human indicate that this protein may be involved in the formation and fusion of transport vesicles from the Golgi. Several transcript variants encoding different isoforms have been described for this gene, however, the full-length nature of not all is known. [provided by RefSeq, Jul 2008]

MANE transcript

NM_014396.4

Inheritance

ClinVar variants

P:11U:134B:13

Top phenotype

Spinocerebellar ataxia, autosomal recessive 29

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr7:38,722,974-38,932,394

External References & Databases

Ensembl (ENSG00000006715)

Transcript & Mutation Effects

hg38 • Region Span ~209.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia, autosomal recessive 29LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030312

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia, autosomal recessive 29STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030312

Submitter: PanelApp Australia

autosomal recessive cerebellar ataxia-saccadic intrusion syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011811

Submitter: Orphanet

spinocerebellar ataxia, autosomal recessive 29MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030312

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 29AR

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: 32808683; 33764426; 33851776

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS41 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 105

not providedTotal: 34

Spinocerebellar ataxia, autosomal recessive 29Total: 18

Hyperimmunoglobulin D with periodic feverTotal: 1

VPS41-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014396.4. 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			3 clinvar	8 clinvar	1 clinvar	12
missense	2 clinvar	2 clinvar	121 clinvar	3 clinvar	1 clinvar	129
nonsense		3 clinvar				3
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	9 clinvar			12
Total	4	7	134	11	2	158

Highest pathogenic variant AF is 0.00019592282

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014396.4	RefSeq	NP_055211.2	29	MANE Select
ENST00000310301.9	Ensembl	ENSP00000309457.4	29	MANE Select
NM_080631.4	RefSeq	NP_542198.2	28	Standard
ENST00000265745.13	Ensembl	ENSP00000265745.9	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ebola Virus Pathway on Host
Ebola Virus Pathway on Host

Biological Process

intracellular protein transport
autophagy
endosome to lysosome transport
endosomal vesicle fusion
regulation of SNARE complex assembly

Molecular Function

protein binding
microtubule binding
identical protein binding
protein self-association
metal ion binding

Cellular Component

lysosomal membrane
early endosome
late endosome
Golgi apparatus
Golgi-associated vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310301
Coding exons: 29
Length: 209432
Individuals with no LoFs: 125522
Homozygous LoFs: 0
Heterozygous LoFs: 224
Defined: 125746
p: 0.000891

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	358	446	0.803	0.0000223	5671
Missense (PolyPhen)		98	133.02	0.73672		1673
Synonymous	-0.387	157	151	1.04	0.00000753	1459
Loss of Function	2.55	37	57.9	0.639	0.00000312	712

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0.0048	0.0048	notable
East Asian	0.0020	0.0020	notable
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00062	0.00062	rare
South Asian	0.00080	0.00075	rare
Other	0.0016	0.0016	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act in part as a core component of the putative HOPS endosomal tethering complex is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE- mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes (PubMed:23351085). Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes implicated in degradation of endocytosed cargo (PubMed:9159129, PubMed:23167963, PubMed:25445562, PubMed:25908847). Required for fusion of autophagosomes with lysosomes (PubMed:25783203). May link the HOPS complex to endosomal Rab7 via its association with RILP and to lysosomal membranes via its association with ARL8B, suggesting that these interactions may bring the compartments to close proximity for fusion (PubMed:25445562, PubMed:25908847). Involved in the direct trans-Golgi network to late endosomes transport of lysosomal membrane proteins independently of HOPS (PubMed:23322049). Involved in sorting to the regulated secretory pathway presumably implicating the AP-3 adaptor complex (By similarity). May play a role in HOPS-independent function in the regulated secretory pathway (PubMed:24210660). {ECO:0000250|UniProtKB:D3ZVH6, ECO:0000269|PubMed:23167963, ECO:0000269|PubMed:23322049, ECO:0000269|PubMed:25445562, ECO:0000269|PubMed:25783203, ECO:0000269|PubMed:25908847, ECO:0000269|PubMed:9159129, ECO:0000305|PubMed:23167963, ECO:0000305|PubMed:23351085, ECO:0000305|PubMed:24210660, ECO:0000305|PubMed:25445562}.;

Recessive Scores

pRec: 0.119

Intolerance Scores

LoFtool: 0.971
RVIS EVS: -0.33
RVIS percentile EVS: 30.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.875

Gene Damage Prediction

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