TOPAZ1

Chr 3

testis and ovary specific TOPAZ 1

Also known as: C3orf77

NCBI Gene: 375337ENSG00000173769UniProt: Q8N9V7OMIM: 614412

TOPAZ1 encodes a protein required for normal spermatogenesis and male fertility, specifically for progression to post-meiotic stages of spermatocyte development and maintaining normal expression levels of testis-expressed gene transcripts. The gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.30), but no human disease phenotypes have been definitively associated with TOPAZ1 mutations to date. Based on the protein's function, mutations would be expected to primarily affect male reproductive function.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismLOEUF 0.30
Clinical Summary— TOPAZ1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
7 unique Pathogenic / Likely Pathogenic· 223 VUS of 260 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.30LOEUF
pLI 0.977
Z-score 6.06
OE 0.19 (0.12–0.30)
Highly constrained

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

Missense Constraint
1.90Z-score
OE missense 0.80 (0.75–0.86)
600 obs / 746.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.19 (0.12–0.30)
0≤0.351.4
Missense OE0.80 (0.75–0.86)
0≤0.61.4
Synonymous OE0.87
0≤1.21.6
LoF obs/exp: 12 / 64.5Missense obs/exp: 600 / 746.2Syn Z: 1.71
DN
0.3991th %ile
GOF
0.4578th %ile
LOF
0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.30

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

260 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic1
VUS223
Likely Benign20
Benign7
Conflicting1
6
Pathogenic
1
Likely Pathogenic
223
VUS
20
Likely Benign
7
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
6
0
6
Likely Pathogenic
0
0
1
0
1
VUS
0
223
0
0
223
Likely Benign
0
20
0
0
20
Benign
0
5
0
2
7
Conflicting
—1
Total024872258

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

View in ClinVar →

Protein Context — Lollipop Plot

TOPAZ1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
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
Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase III TOPAZ-1 study.
Oh DY et al.·J Hepatol
2025Clinical trial
Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study.
Oh DY et al.·Lancet Gastroenterol Hepatol
2022Clinical trial
Genetics of sleep medication purchases suggests causality from sleep problems to psychiatric traits.
Broberg M et al.·Sleep
2024
Exploring the impact of durvalumab on biliary tract cancer: insights from real-world clinical data.
Reimann P et al.·Cancer Immunol Immunother
2024
Efficacy, safety and differential outcomes of immune-chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort.
Mitzlaff K et al.·United European Gastroenterol J
2024Cohort
Top 5 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