MARCHF6

Chr 5AD

membrane associated ring-CH-type finger 6

Also known as: DOA10, FAME3, FCMTE3, MARCH-VI, MARCH6, RNF176, TEB4

NCBI Gene: 10299ENSG00000145495UniProt: O60337

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]

Primary Disease Associations & Inheritance

Epilepsy, familial adult myoclonic, 3MIM #613608
AD
0
Active trials
100
Pathogenic / LP
194
ClinVar variants
12
Pubs (1 yr)
3.9
Missense Z· constrained
0.15
LOEUF· LoF intolerant
Clinical Summary— MARCHF6
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
100 Pathogenic / Likely Pathogenic· 91 VUS of 194 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.15LOEUF
pLI 1.000
Z-score 6.71
OE 0.07 (0.03–0.15)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
3.88Z-score
OE missense 0.52 (0.47–0.57)
263 obs / 509.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.07 (0.03–0.15)
0≤0.351.4
Missense OE0.52 (0.47–0.57)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 4 / 60.2Missense obs/exp: 263 / 509.0Syn Z: 0.61
LOFGOF
DN
0.5673th %ile
GOF
0.6443th %ile
LOF
0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.15
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic100
VUS91
Likely Benign3
100
Pathogenic
91
VUS
3
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
100
0
100
Likely Pathogenic
0
0
0
0
0
VUS
1
81
8
1
91
Likely Benign
0
1
1
1
3
Benign
0
0
0
0
0
Total1821092194

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

MARCHF6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 4 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients