Identifying gene mutation signatures will enable a better understanding for the occurrence, development, and prognosis of hepatocellular carcinoma (HCC) and provide some potential biomarkers for clinical practice. This study investigated the mutated genes in HCC patients and assessed their relationship with tumor mutation burden (TMB) and prognosis. The somatic mutation annotation format (MAF) document, mRNA expression matrix, and clinical information of HCC patients were obtained from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) database. The differences of TMB between the mutant type and the wild-type genes were detected using the Mann-Whitney U test. The link of gene mutations with prognosis was explored by the Kaplan-Meier analysis. The proportion of 22 immune cells' composition was measured using CIBERSORT algorithm. The two databases screened 16 common mutated genes, which included TP53, TTN, LRP1B, ZFHX4, MUC16, OBSCN, CSMD3, FLG, CSMD1, SYNE1, SPTA1, USH2A, KMT2C, PCLO, HMCN1, and FAT3. After a series of analysis, MUC16 mutation was found to be highly correlated with TMB and was regarded as an independent factor predicting HCC. Furthermore, gene set enrichment analysis (GSEA) indicated that the MUC16 mutation was significantly involved in HCC cell metabolism. MUC16 mutation seems to be a valuable potential biomarker for HCC development and its overall survival.