TRIM8

Chr 10AD

tripartite motif containing 8

Also known as: FSGSNEDS, GERP, RNF27

NCBI Gene: 81603 ENSG00000171206 UniProt: Q9BZR9 OMIM: 606125

The protein functions as an E3 ubiquitin-protein ligase that regulates innate immune signaling pathways, including interferon-gamma, TNF-alpha, and IL-1beta responses, by targeting specific proteins for ubiquitination and degradation. Mutations cause focal segmental glomerulosclerosis and neurodevelopmental syndrome with autosomal dominant inheritance, affecting both kidney and neurological development. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.26), indicating that most protein-truncating variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the tripartite motif (TRIM) protein family. Based on similarities to other proteins, the encoded protein is suspected to be an E3 ubiquitin-protein ligase. Regulation of this gene may be altered in some cancers. Mutations resulting in a truncated protein product have been observed in early-onset epileptic encephalopathy (EOEE). [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— TRIM8

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Gene-Disease Validity (ClinGen)

focal segmental glomerulosclerosis and neurodevelopmental syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

24 unique Pathogenic / Likely Pathogenic· 190 VUS of 463 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.994

Z-score 4.18

OE 0.08 (0.03–0.26)

Highly constrained

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

Missense Constraint?

2.74Z-score

OE missense 0.58 (0.52–0.66)

198 obs / 340.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.26)

0≤0.351.4

Missense OE?0.58 (0.52–0.66)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 2 / 24.2Missense obs/exp: 198 / 340.3Syn Z: 1.42

ClinVar Variant Classifications

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic11

VUS190

Likely Benign210

Benign16

Conflicting15

Pathogenic

Likely Pathogenic

190

VUS

210

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	0	0	0	13
Likely Pathogenic	11	0	0	0	11
VUS	11	176	2	1	190
Likely Benign	0	43	30	137	210
Benign	0	5	6	5	16
Conflicting	—				15
Total	35	224	38	143	455

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap TRIM8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →