Silent mutations in medical genetics databases like ClinVar contain extra value if analyzed with the most current genomics tools. In most cases the silent mutations are of low priority in big data genomics analysis, unless additional value like them being found at functionally important DNA sequences accompanies them. This presentation describes a method to add value to the silent mutations in human exome. Specifically, mapping variants, including silent variants to the known exon-intron boundaries identifies the silent mutations whose potential as pathogenic would otherwise be a lot more unclear.
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Hidden value in medical genetics databases. Splice the silence!
1. Mehis Pold, MD
Email:mehisp@hotmail.com
1
THEY AREN’T PERFECT! WIDELY USED GENOMICS
DATABASES THAT IS…DIG DEEP!
By Mehis Pold, MD
Public databases have become one of the most used sources for information in
genomics data analysis. They too, as anything else in this world aren’t perfect
though. Case in point – ClinVar.
I mapped all ClinVar GRCh37 single nucleotide variants using my UVM (Universal
Variation Mapping) tools to known exon-intron boundaries as provided by CCDS. My
particular interest was to find ClinVar variants annotated as silent mutations but
located at conserved positions on splice junctions (see below, Fig. 1). A silent
mutation found at a conserved position of an exon-intron boundary is certainly of
higher value for interpretation of genetic finding than just a silent mutation
anywhere else on an exon. In brief, I was curious if I could add value to the silent
variants described in ClinVar.
RESULT: I found a total of 2,426 GRCh37 variants in ClinVar not annotated for
conserved splice junction positions. Out of these 2,426 variants, 159 were
annotated as silent mutations (please see below, Table 1 and 2 for more descriptive
details). For me in particular, the silent mutations on BRCA1 and BRCA2 stood out.
CONCLUSION: Anyone using public databases still needs additional tools in order
to uncover the full value found therein. Just relying on the annotations provided in
the public databases will result in overlooking important details.
Figure 1. Mapping was carried out to conserved positions on exon-intron
boundaries. E – exon, I – intron, 1 – first position, 2 –second position, z – last
position, y – second last position.
Ez I1 I2 Iy Iz E1
+1 -1 -2 -2 -1 +1
DONOR SITE ACCEPTOR SITE
Exon Intron Exon
Conserved positions
2. Mehis Pold, MD
Email:mehisp@hotmail.com
2
Table 1. Summary of ClinVar variant mapping to the known exon-intron
boundaries as provided by CCDS.
Total number of entries annotated as CRCh37: 97,811
Variants, no annotation to splice junction: 2426/97,811 = 2.5%
Silent coding region variants, no annotation to splice junction: 159/97,811 =
0.16%
Location on
splice
junction
Number of
hits in
ClinVar
Number of hits
with ClinVar silent
mutation
Splice junction description key
E1_A_MINUS 166 19 E1 - first base on exon
E1_A_PLUS 191 22 Ez - last base on exon
Ez_D_MINUS 245 39 I1 - first base on intron
Ez_D_PLUS 246 73 I2 - second base on intron
I1_D_MINUS 309 3 Iy - second last base on intron
I1_D_PLUS 315 0 Iz - last base on intron
I2_D_MINUS 92 1 A - acceptor
I2_D_PLUS 140 2 D - donor
Iy_A_MINUS 154 0 MINUS - minus strand
Iy_A_PLUS 175 0 PLUS - plus strand
Iz_A_MINUS 178 0
Iz_A_PLUS 215 0
TOTALS 2426 159
Source file: ClinVar database, variant summary, downloaded 06242014
Genome assembly - CRCh37
Variant type: single nucleotide variant
Source for exon-Intron boundary coordinates: CCDS
Table 2. The list of ClinVar silent mutations mapping to the conserved positions on
exon-intron boundaries.
E1_A_MINUS
Variant Description Gene ID Pathogenicity
Genome
Coordinates
AGA:c.699C>T (p.Gly233Gly=) AGA not provided 4:178355643
ATP4A:c.2007G>A (p.Lys669Lys=) ATP4A not provided 19:36046492
COBL:c.246C>T (p.Ser82Ser=) COBL not provided 7:51261286
MMP1:c.351G>A (p.Arg117Arg=) MMP1 not provided 11:102667893
MYH1:c.4182G>A (p.Lys1394Lys=) MYH1 not provided 17:10401234
NLRP13:c.2958G>A (p.Gly986=) NLRP13 not provided 19:56407485
NPHP3:c.1986G>A (p.Arg662=) NPHP3 Benign 3:132416206
PDE4C:c.243C>T (p.Arg81Arg=) PDE4C not provided 19:18333133