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1.Brief introduction

Synonymous substitution (which is often called silent mutation before) is a kind of point mutation occurs in genes' coding region. Because the codons' degeneracy, it does not alter the Amino acid residue. As a result, for a long time, it's considered no bio function, treated as "silent".

But recent research shows "Silent Mutation Make Some Noise", and makes people focus on the area. Efforts have been made, one possible mechanism has been proposed, and synonymous mutations specifically change the splicing motifs and cause abnormal splicing.

However, there is no database focusing on the dangerous of synonymous mutations yet. Therefore, we have collected diseases related mutation to construct a Database of Deleterious Synonymous mutation (dbDSM) that would help in understanding the relationship between diseases and the synonymous mutations. Here we present the updated dbDSMv2.0 database, which newly added the tmVar data and updated ClinVar, GWAS Catalog data. In the new version of the database, we added new annotation features, including transcripts, conservatism, etc and we used the voting method to integrate the scores of the five scoring tools (SilVA, DDIG-SN, FATHMM-MKL, CADD, and TraP) which is named dbDSMScore to further assess the deleterious of the variants. Notably, variants from the original literature are marked in red.

2.The sources of the data

Data source dbDSMv1.0 dbDSMv2.0
1.Manually curated Yes Yes
2.GRASP Yes Yes
3.ClinVar Yes Yes
4.PolymiRTS Yes Yes
5.GWAS catalog Yes Yes
6.GWASdb Yes Yes
7.tmVar No Yes

3.The sum of the data

SNPs Number of records in dbDSMv1.0 Number of records in dbDSMv2.0
With ref ID 1219 2116
Without ref ID 116 631
Total 1335 2747

4.The DSMs classification

To the best of our knowledge, there is no consensus classification of molecular mechanisms by which synonymous mutations contribute to disease phenotype. Therefore, after reviewing the literature (Bali and Bebok, 2015; Gotea et al, 2015; Hunt et al, 2014; Sauna and Kimchi-Sarfaty, 2011), we used a classification system in the database as follows:
Classification Description
Splicing regulation Synonymous mutations may disrupt critical elements necessary for splicing, which could result in multiple outcomes, such as exon truncation, exon skipping, and intron inclusion.
mRNA structure Synonymous mutations can alter mRNA structure, which in turn can change transcript stability and translation dynamics.
microRNA binding Synonymous mutations can change the nucleotide sequence recognized by microRNAs, which can alter gene expression levels.
Transcription factor regulation Synonymous mutations can add or subtract exonic transcription factor binding sites, leading to altered gene expression levels.
Protein synthesis Protein translation and folding can also be influenced by synonymous mutations through codon usage (rare versus frequent codons), tRNA availability, mRNA shape, and ribosome structure.
n/a If the mechanism is not available, the classification information is indicated as n/a.


Bali, V., & Bebok, Z. (2015). Decoding mechanisms by which silent codon changes influence protein biogenesis and function. The International Journal of Biochemistry & Cell Biology, 64, 58-74.

Gotea, V., Gartner, J. J., Qutob, N., Elnitski, L., & Samuels, Y. (2015). The functional relevance of somatic synonymous mutations in melanoma and other cancers. Pigment Cell & Melanoma Research, 28(6), 673-684.

Hunt, R. C., Simhadri, V. L., Iandoli, M., Sauna, Z. E., & Kimchi-Sarfaty, C. (2014). Exposing synonymous mutations. Trends in Genetics, 30(7), 308-321.

Sauna, Z. E., & Kimchi-Sarfaty, C. (2011). Understanding the contribution of synonymous mutations to human disease. Nature Reviews Genetics, 12(10), 683-691.

5.Strength of evidence for variant assessment

Evidence leading to a pathogenic assertion Strength of evidence
Significant segregation in affected family members (LOD >2) 3
Confirmed de novo inheritance in relevant disease-associated gene 3
In vivo data from mammalian model organisms suggest an impact on function 2
Case-control studies significantly associate the variant to disease 2
Nucleotide and amino acid strongly conserved in distantly related species 2
In vitro data from recombinant DNA constructs or proteins suggest an impact on function 1
Variant is present in trans with an established pathogenic variant in recessive disease 1
Variant is rare or absent in large population studies 1
Computational tools predict an impact on function and/or splicing 1


Duzkale, H., Shen, J., McLaughlin, H., Alfares, A., Kelly, M. A., Pugh, T. J., ... & Lebo, M. S. (2013). A systematic approach to assessing the clinical significance of genetic variants. Clinical genetics, 84(5), 453-463.

6. The annotation tools used in dbDSMv2.0

Tool Genomic build Source Threshold Ref
SilVA GRCh37/hg19 http://compbio.cs.toronto.edu/silva >0.278 [1]
DDIG-SN GRCh37/hg19 http://sparks-lab.org/ddig >0.5 [2]
FATHMM-MKL GRCh37/hg19 http://fathmm.biocompute.org.uk >0.5 [3]
TraP GRCh37/hg19 http://trap-score.org/Search?version=v2 ≧0.459 [4]
CADD GRCh37/hg19 https://myvariant.info 10-20 [5]
GERP++ GRCh37/hg19 https://myvariant.info >0 [5]
Phylop100way GRCh38/37 http://genome.ucsc.edu/cgi-bin/hgTables >0 [6]
PhastCons100way GRCh38/37 http://genome.ucsc.edu/cgi-bin/hgTables >0.5 [6]
TransVar GRCh38/37 http://bioinformatics.mdanderson.org/transvarweb/ - [7]
VEP GRCh38/37 http://www.ensembl.org/Tools/VEP - [8]


[1] Buske, O. J., Manickaraj, A., Mital, S., Ray, P. N., & Brudno, M. (2013). Identification of deleterious synonymous variants in human genomes. Bioinformatics, 29(15), 1843-1850.

[2] Livingstone, M., Folkman, L., Yang, Y., Zhang, P., Mort, M., Cooper, D. N., ... & Zhou, Y. (2017). Investigating DNA‐, RNA‐, and protein‐based features as a means to discriminate pathogenic synonymous variants. Human mutation, 38(10), 1336-1347.

[3] Shihab, H. A., Rogers, M. F., Gough, J., Mort, M., Cooper, D. N., Day, I. N., ... & Campbell, C. (2015). An integrative approach to predicting the functional effects of non-coding and coding sequence variation. Bioinformatics, 31(10), 1536-1543.

[4] Gelfman, S., Wang, Q., McSweeney, K. M., Ren, Z., La Carpia, F., Halvorsen, M., ... & Petrovski, S. (2017). Annotating pathogenic non-coding variants in genic regions. Nature communications, 8(1), 236.

[5] Xin, J., Mark, A., Afrasiabi, C., Tsueng, G., Juchler, M., Gopal, N., ... & Torkamani, A. (2016). High-performance web services for querying gene and variant annotation. Genome biology, 17(1), 91.

[6] http://genome.ucsc.edu/cgi-bin/hgTables

[7] Zhou, W., Chen, T., Chong, Z., Rohrdanz, M. A., Melott, J. M., Wakefield, C., ... & Chen, K. (2015). TransVar: a multilevel variant annotator for precision genomics. Nature methods, 12(11), 1002.

[8] McLaren, W., Gil, L., Hunt, S. E., Riat, H. S., Ritchie, G. R., Thormann, A., ... & Cunningham, F. (2016). The ensembl variant effect predictor. Genome biology, 17(1), 122.

7.The overview of the searching process

The browse process including “Search” and “Advanced search”.


You can input one keyword to search the dbDSM. The search fields include disease name, gene name, GRCh38 genome position, deleterious synonymous mutation (c.DNA, protein, rsid).

2) Advanced search

You can select one or more of the four options listed in the browse area (Gene, Disease, dbDSMScore, Chromosome).

8.Statistics dbDSMScore

Data Release
Data release of dbDSM v2
ClinVar Description Public archive of interpretations of clinically relevant variants
Download ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/tab_delimited/
Release 2018/07/09
GRASP Description Genome-Wide Repository of Associations Between SNPs and Phenotypes
Download https://s3.amazonaws.com/NHLBI_Public/GRASP/GraspFullDataset2.zip
Release GRASP
GWAS Catalog Description The NHGRI-EBI Catalog of published genome-wide association studies
Download http://www.ebi.ac.uk/gwas/downloads
Release v1.0.2 _e92_r2018/06/25
PolymiRTS 3.0 Description Polymorphism in microRNAs and their TargetSites
Download http://compbio.uthsc.edu/miRSNP/download/
Release PolymiRTS3.0_2013/07/22
GWASdb Description A database for human genetic variants identified by genome-wide association studies
Download http://jjwanglab.org/gwasdb
Release 2015/08
Manually curated Description An extensive literature query of PubMed database and Web of Knowledge using a list of keywords
Download PubMed database and Web of Knowledge
Release 2015/12/31
tmVar Description tmVar extracts a wide range of sequence variants in both protein and gene levels (e.g. substitution, deletion, etc) in HGVS formats
Download ftp://ftp.ncbi.nlm.nih.gov/pub/lu/PubTator/
Release 2017/12/09

Brief release history

 07/06/2019: The Database of Deleterious Synonymous Mutation Version 2 (dbDSM v2) is updating.

 08/31/2018: Data from tmVar added and ClinVar,GWAS Catalog updated.

 09/21/2017: Manually curated data from PubMed and Web of Knowledge updated.

 01/21/2016: Nearly one hundred entries were updated into dbDSM.

 01/18/2016: Download page updated.

 01/17/2016: Data in dbDSM were updated based on the comments from anonymous reviewers.

 11/17/2015: Data from GRASdb added.

 11/11/2015: Home page updated.

 10/15/2015: Document page updated.

 10/07/2015: Submit page updated.

 09/20/2015: Release the dbDSM.

 Fields statistics
Field Description
dbDSMAccNum The access number of a variant in dbDSM
Gene Gene name
GeneID The unique identifier for a gene
MIM The identifier of a gene linked to OMIM database
Map_Location The map location for this gene
VariantType Germline or somatic mutation
Disease The main phenotype of the patient
DOID The identifier of a disease linked to OMIM database
SNPID dbSNP identifier of the variant. If there is no rs id this field is “n/a“
GRCh38_Position Genomic position in GRCh38
GRCh37_Position Genomic position in GRCh37
Ref Reference allele
Alt Alternate allele
Strand A variant occurred in forword chain(+) or reverse chain(-)
c.DNA A coding reference level representation of the variant
Protein A protein reference level representation of the variant
CodonChange Reference codon > Alternate codon
RefseqTranscript Refseq Transcript that the variant resides on
P_Value P-value in GWAS
PhyloP100way 100 Vertebrate Phylop conservation score at mutation position
PhastCons100way 100 Vertebrate PhastCons conservation score at mutation position
GerpS Rejected Substitution' score defined by GERP++
Source The source of a variant
dbDSMScore dbDSM score of a variant Which are including SilVA,DDIG-SN,FATHMM-MKL, TraP, CADD score.We use voting methods to evaluate the variant, dbDSM score plus one if the score above the threshold value for each tool.
PMID Pubmed ID for an article
Year Published time of an article
KeySentence Deleterious evidence of a variant extracted from the article
Classification Deleterious mechanism of a variant
StrengthOfEvidence Clinical classification of a variant
Data statistics
Entries Disease 1499
Gene 1624
Variants 2747
Chromosomal location Variants Entries mapped to chromosome 1 258
Variants Entries mapped to chromosome 2 163
Variants Entries mapped to chromosome 3 136
Variants Entries mapped to chromosome 4 90
Variants Entries mapped to chromosome 5 95
Variants Entries mapped to chromosome 6 216
Variants Entries mapped to chromosome 7 119
Variants Entries mapped to chromosome 8 67
Variants Entries mapped to chromosome 9 92
Variants Entries mapped to chromosome 10 99
Variants Entries mapped to chromosome 11 183
Variants Entries mapped to chromosome 12 133
Variants Entries mapped to chromosome 13 64
Variants Entries mapped to chromosome 14 50
Variants Entries mapped to chromosome 15 102
Variants Entries mapped to chromosome 16 134
Variants Entries mapped to chromosome 17 178
Variants Entries mapped to chromosome 18 26
Variants Entries mapped to chromosome 19 137
Variants Entries mapped to chromosome 20 46
Variants Entries mapped to chromosome 21 26
Variants Entries mapped to chromosome 22 49
Variants Entries mapped to chromosome X 109
Variants Entries mapped to chromosome Y 0
Variants Entries mapped to chromosome MT 1
Publications tmVar publications 2548
ClinVar publications 510
GRASP publications 196
GWASdb publications 357
PolymiRTS publications 80
GWAS Catalog publications 179
Manual Read publications 195