In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects

Lastella, Patrizia; Surdo, Nicoletta Concetta; Resta, Nicoletta; Guanti, Ginevra; Stella, Alessandro

doi:10.1186/1471-2164-7-243

Table 1 Pathogenic Missense Mutations analyzed in the splicing assay

From: In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects

					NNSPLICE^e		SpliceSite Finder^f
Mutation^a	Exon	ESEfinder^b	Rescue ESE^c	PESX^d	SA	SD	SA+BPS	SD	GENSCAN Exon P-value^g	Dist. from the nearest SS	Exon size (bp)	Mutation effect on splicing
hMSH2
A308G	2	SRp40 3.05>0	0	0	0.99	1	170.8	85.6	0.998(0.998)	-58	155	=
A593G	3	SF2 3.67>2.80 +SRp40	-2/2	0	0.98	1	161.5	94.2	0.861(0.861)	-52	279	=
C806T	5	SRp55 2.67>0	-1/1	+1/0 PESS	0.96	0.92	NI	79.9	0.987(0.985)	+14	150	↓
C815T	5	SF2 3.2>0 SRp55 2.7>0	0	-1/1 PESS	0.96	0.92	NI	79.9	0.987(0.985)	+23	150	↓
G965A (3)	6	SC35 3.39>3.03 SRp40 5.72>3.34	0	+1/0 PESE	0.98	0.98	187.8	88.7	0.999(0.999)	+24	134	=
G1012A	6	SF2 2.2>0 SC35 2.6>0 SRp404.3>0	+2/5	-1/1 PESE	0.98	0.98	187.8	88.7	0.999(0.999)	-64	134	=
G1516T	10	SC35 5.44>4.79 + SC35	0	-4/4 PESE	NI	0.60	150.5	72.8	0.991(0.991)	+6	151	↓
G1571C	10	SRp55 3.3>0 + SC35	0	0	NI	0.60	150.5	72.8	0.991(0.991)	+61	151	=
C1600T	10	SRp55 3.4>0	0	+1/0 PESS	NI	0.60	150.5	72.8	0.991(0.991)	-61	151	↓
hMLH1
G199A (8)	2	SF2 4.26>2.34 +1SF2 +1 SC35	0	0	0.86	1	180.4	92.2	0.790/0.789	-8	91	=
G200A (2)	2	SF2 4.26>0	-1/7	0	0.86	1	180.4	92.2	0.790/0.789	-7	91	=
T320G	4	SRp55 3.3 >0 + SF2 2.8	+4/1	+3/0 PESE	1	0.88	155.6	69.7	0.987/0.990	+14	74	=
G731A	9	SRp40 3.7>0	0	-3/3 PESS	0.88	0.96	156.4	78.3	0.338/0.205 term	+54	113	=
C793T (2)	10	SRp40 3.85>4.2	0	0	0.99	0.93	167.8/171	81.0	NI/NI	+4	94	=
C842T	10	SF2 3.2>0 SC35 2.6>0 SRp55 4.7>3.1+SRP55	0	= 1 PESS	0.99	0.93	167.8	81.0	NI/NI	-42	94	↓
G1569T	14	0	-3/3	0	0.98/0.97	0.99	182.3	85.6	0.912/0.976	+11	109	=
T1958G	17	SF2 2.1= SRp55 3.5>0 + SF2	0	0	NI	0.91	166.6	90.0	0.836/0.877	-31	93	↑
C1961T	17	SF2 2.1>0 SRp55 = +SC35	0	0	NI	0.91	166.6	90.0	0.836/0.828	-28	93	=
A1963G	17	SF2 2.1> 0 SRp55 3.5>0	-1/2	+1/0 PESE	NI	0.91	166.6	90.0	0.836/0.857	-26	93	↑
G1976C (3)	17	SRp40 4.3>5.15+SC35	0	0	NI	0.91	166.6	90.0	0.836/0.490	-13	93	↓

^a in parenthesis the number of families/cases in the database presenting the mutation.
^b effect of the mutation on the scores as predicted by the algorithm.
^c number of ESE motifs added or abrogated from the mutation/number of ESE motifs in the normal allele.
^d number of enhancer (PESE) or suppressor (PESS) sequences added or abrogated from the mutation/number of PESE or PESS in the normal allele.
^e SA = splice acceptor, SD = splice donor, NI = not identified as corresponding splicing site by the program, in italics are indicated the suboptimal scores.
^f SA+BPS = splice acceptor + branch point sites, NI = not identified as corresponding splicing site by the program, in italics are indicated the suboptimal scores.
^g in parenthesis the score for the wild type allele; term = the exon is recognized as a terminal exon.
In bold the mutations significantly altering splicing: = no change in exon inclusion; ↑ = increase in exon inclusion; ↓ = increase in exon skipping.

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ISSN: 1471-2164

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