MARCHF6

protein-coding

membrane associated ring-CH-type finger 6, the group of Membrane associated ring-CH-type fingers|Ring finger proteins

Gene summary

This gene encodes a member of a family of membrane-associated E3 ubiquitin ligases containing RING-CH-type zinc finger motifs. Ubiquitination of type II deiodinase by the encoded protein is an important regulatory step in thyroid hormone signalling. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

Previous symbols:

MARCH6

MANE transcript

NM_005885.4

Inheritance

ClinVar variants

U:110B:6

Top phenotype

Epilepsy, familial adult myoclonic, 3

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr5:10,353,695-10,440,388

External References & Databases

Ensembl (ENSG00000145495)

Transcript & Mutation Effects

hg38 • Region Span ~86.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

benign adult familial myoclonic epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019448

Submitter: Orphanet

Clinical Genomic Database (CGD)

Epilepsy, familial adult myoclonic, 3AD

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: 14978679; 20548044; 31664039

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MARCHF6 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 87

Epilepsy, familial adult myoclonic, 3Total: 5

not providedTotal: 4

Spastic diplegiaTotal: 1

MARCHF6-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005885.4. 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			4 clinvar	5 clinvar		9
missense			91 clinvar	1 clinvar		92
nonsense			3 clinvar			3
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	110	6	0	116

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005885.4	RefSeq	NP_005876.2	26	MANE Select
ENST00000274140.10	Ensembl	ENSP00000274140.4	26	MANE Select
NM_001270660.2	RefSeq	NP_001257589.1	25	Standard
NM_001270661.2	RefSeq	NP_001257590.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
ER Quality Control Compartment (ERQC)
Calnexin/calreticulin cycle
Post-translational protein modification
Metabolism of proteins

Biological Process

proteasomal protein catabolic process
ubiquitin-dependent ERAD pathway
ERAD pathway
protein K48-linked ubiquitination
endoplasmic reticulum mannose trimming

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding
enzyme binding
ubiquitin conjugating enzyme binding

Cellular Component

ER ubiquitin ligase complex
endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274140
Coding exons: 26
Length: 86686
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.88	263	509	0.517	0.0000277	5889
Missense (PolyPhen)		44	164.74	0.26708		1979
Synonymous	0.612	176	187	0.943	0.0000105	1818
Loss of Function	6.71	4	60.2	0.0664	0.00000343	638

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000041	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000060	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that promotes ubiquitination of DIO2, leading to its degradation. 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. May cooperate with UBE2G1. {ECO:0000269|PubMed:15673284, ECO:0000269|PubMed:19651899}.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.207
RVIS EVS: -0.56
RVIS percentile EVS: 19.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.641

Gene Damage Prediction

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