MARCHF4

protein-coding

membrane associated ring-CH-type finger 4, the group of Ring finger proteins|Membrane associated ring-CH-type fingers

Gene summary

MARCH4 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH enzymes add ubiquitin (see MIM 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH4 reduces surface accumulation of several membrane glycoproteins by directing them to the endosomal compartment (Bartee et al., 2004 [PubMed 14722266]).[supplied by OMIM, Apr 2010]

Previous symbols:

MARCH4

MANE transcript

NM_020814.3

Inheritance

—

ClinVar variants

U:51B:7

Top phenotype

Frontotemporal dementia

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr2:216,257,865-216,372,483

External References & Databases

Ensembl (ENSG00000144583)

Transcript & Mutation Effects

hg38 • Region Span ~114.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MARCHF4 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 55

Frontotemporal dementiaTotal: 2

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020814.3. 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	1
missense			51 clinvar	6 clinvar		57
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	51	6	1	58

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020814.3	RefSeq	NP_065865.1	4	MANE Select
ENST00000273067.5	Ensembl	ENSP00000273067.3	4	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein ubiquitination

Molecular Function

ubiquitin-protein transferase activity
zinc ion binding

Cellular Component

Golgi membrane
Golgi stack
trans-Golgi network
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273067
Coding exons: 4
Length: 114163
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	196	247	0.795	0.0000144	2628
Missense (PolyPhen)		48	75.474	0.63598		800
Synonymous	-0.852	114	103	1.11	0.00000644	835
Loss of Function	2.92	5	18.6	0.269	8.39e-7	193

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00013	rare
South Asian	0.00030	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I and CD4, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin- conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. {ECO:0000269|PubMed:14722266}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.317
RVIS EVS: -0.67
RVIS percentile EVS: 15.62

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.149

Gene Damage Prediction

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