Incidental Mutation 'R7181:Prex1'
| ID |
558963 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Prex1
|
| Ensembl Gene |
ENSMUSG00000039621 |
| Gene Name |
phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 |
| Synonyms |
P-REX1 |
| MMRRC Submission |
045270-MU
|
| Accession Numbers |
|
| Essential gene? |
Probably non essential
(E-score: 0.188)
|
| Stock # |
R7181 (G1)
|
| Quality Score |
225.009 |
|
Status
|
Validated
|
| Chromosome |
2 |
| Chromosomal Location |
166408265-166555752 bp(-) (GRCm39) |
| Type of Mutation |
missense |
| DNA Base Change (assembly) |
G to A
at 166412291 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
Alanine to Valine
at position 1568
(A1568V)
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000037180
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000036719]
[ENSMUST00000099080]
[ENSMUST00000109246]
|
| AlphaFold |
Q69ZK0 |
| Predicted Effect |
probably damaging
Transcript: ENSMUST00000036719
AA Change: A1568V
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
| SMART Domains |
Protein: ENSMUSP00000037180
Gene: ENSMUSG00000039621
AA Change: A1568V
| Domain | Start | End | E-Value | Type |
|---|
|
low complexity region
|
3 |
27 |
N/A |
INTRINSIC |
|
RhoGEF
|
48 |
234 |
3.16e-52 |
SMART |
|
PH
|
267 |
389 |
1.02e-10 |
SMART |
|
DEP
|
418 |
491 |
6.86e-27 |
SMART |
|
DEP
|
519 |
592 |
3.06e-24 |
SMART |
|
PDZ
|
628 |
701 |
4.55e-1 |
SMART |
|
PDZ
|
712 |
783 |
5.66e-1 |
SMART |
|
low complexity region
|
800 |
811 |
N/A |
INTRINSIC |
|
low complexity region
|
814 |
825 |
N/A |
INTRINSIC |
|
low complexity region
|
1109 |
1127 |
N/A |
INTRINSIC |
|
low complexity region
|
1545 |
1555 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably damaging
Transcript: ENSMUST00000099080
AA Change: A1398V
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
| SMART Domains |
Protein: ENSMUSP00000096679
Gene: ENSMUSG00000039621
AA Change: A1398V
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:RhoGEF
|
5 |
64 |
3.8e-18 |
PFAM |
|
PH
|
97 |
219 |
1.02e-10 |
SMART |
|
DEP
|
248 |
321 |
6.86e-27 |
SMART |
|
DEP
|
349 |
422 |
3.06e-24 |
SMART |
|
PDZ
|
458 |
531 |
4.55e-1 |
SMART |
|
PDZ
|
542 |
613 |
5.66e-1 |
SMART |
|
low complexity region
|
630 |
641 |
N/A |
INTRINSIC |
|
low complexity region
|
644 |
655 |
N/A |
INTRINSIC |
|
low complexity region
|
939 |
957 |
N/A |
INTRINSIC |
|
low complexity region
|
1375 |
1385 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably damaging
Transcript: ENSMUST00000109246
AA Change: A380V
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
| SMART Domains |
Protein: ENSMUSP00000104869
Gene: ENSMUSG00000039621
AA Change: A380V
| Domain | Start | End | E-Value | Type |
|---|
|
low complexity region
|
357 |
367 |
N/A |
INTRINSIC |
|
| Meta Mutation Damage Score |
0.8208 |
| Coding Region Coverage |
- 1x: 100.0%
- 3x: 99.9%
- 10x: 99.6%
- 20x: 98.9%
|
| Validation Efficiency |
98% (62/63) |
| MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene acts as a guanine nucleotide exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a null allele have impaired neutrophil migration and autism-like social behavior with defective AMPA-mediated LTD. Mice with other alleles exhibit reduced weight, smaller livers and increased peripheral neutrophil numbers. [provided by MGI curators]
|
| Allele List at MGI |
|
| Other mutations in this stock |
Total: 62 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Acsbg3 |
A |
G |
17: 57,188,037 (GRCm39) |
N182D |
probably benign |
Het |
| Adgrl1 |
A |
G |
8: 84,652,878 (GRCm39) |
|
probably null |
Het |
| Adm |
T |
C |
7: 110,228,236 (GRCm39) |
I139T |
probably damaging |
Het |
| Ahnak |
A |
T |
19: 8,990,852 (GRCm39) |
K4045N |
probably damaging |
Het |
| Axin1 |
T |
A |
17: 26,392,752 (GRCm39) |
S344R |
probably damaging |
Het |
| Cacna1g |
T |
C |
11: 94,306,691 (GRCm39) |
S1896G |
probably benign |
Het |
| Cd209c |
A |
G |
8: 3,995,712 (GRCm39) |
V30A |
probably benign |
Het |
| Cd86 |
CA |
CAA |
16: 36,426,917 (GRCm39) |
|
probably null |
Het |
| Cdh8 |
A |
T |
8: 99,825,557 (GRCm39) |
M520K |
probably benign |
Het |
| Cyp2b23 |
G |
A |
7: 26,373,828 (GRCm39) |
T306I |
probably damaging |
Het |
| Dnajc10 |
T |
G |
2: 80,149,587 (GRCm39) |
Y96* |
probably null |
Het |
| Eif1ad14 |
G |
A |
12: 87,886,492 (GRCm39) |
R46W |
possibly damaging |
Het |
| Elmod1 |
A |
C |
9: 53,841,382 (GRCm39) |
|
probably null |
Het |
| Eva1b |
A |
G |
4: 126,043,446 (GRCm39) |
H162R |
possibly damaging |
Het |
| Fam222b |
A |
T |
11: 78,045,804 (GRCm39) |
N455I |
probably damaging |
Het |
| Fer1l6 |
G |
A |
15: 58,447,146 (GRCm39) |
A626T |
probably benign |
Het |
| Fgd6 |
A |
G |
10: 93,879,373 (GRCm39) |
T76A |
probably benign |
Het |
| Fndc7 |
A |
G |
3: 108,788,640 (GRCm39) |
|
probably null |
Het |
| Gabrg2 |
T |
A |
11: 41,811,261 (GRCm39) |
I295F |
probably damaging |
Het |
| Gm10406 |
A |
T |
14: 7,027,359 (GRCm38) |
|
probably null |
Het |
| Gm47189 |
T |
C |
14: 41,492,059 (GRCm39) |
M73V |
probably benign |
Het |
| Gm9758 |
A |
T |
5: 14,963,667 (GRCm39) |
S54T |
probably damaging |
Het |
| Gm9857 |
A |
G |
3: 108,847,554 (GRCm39) |
S70P |
unknown |
Het |
| Gsap |
A |
T |
5: 21,458,427 (GRCm39) |
E470D |
probably damaging |
Het |
| Hesx1 |
T |
A |
14: 26,722,678 (GRCm39) |
M1K |
probably null |
Het |
| Hirip3 |
A |
G |
7: 126,463,235 (GRCm39) |
D397G |
probably damaging |
Het |
| Kalrn |
T |
A |
16: 33,983,447 (GRCm39) |
N13I |
probably benign |
Het |
| Mettl8 |
A |
T |
2: 70,803,706 (GRCm39) |
S194T |
possibly damaging |
Het |
| Mrps35 |
T |
G |
6: 146,957,491 (GRCm39) |
|
probably null |
Het |
| Myrfl |
G |
T |
10: 116,697,448 (GRCm39) |
N25K |
probably damaging |
Het |
| Or51b6b |
C |
A |
7: 103,310,020 (GRCm39) |
G146C |
probably damaging |
Het |
| Or7a41 |
A |
G |
10: 78,871,287 (GRCm39) |
Y219C |
probably damaging |
Het |
| Or9k2b |
A |
T |
10: 130,016,626 (GRCm39) |
I41N |
possibly damaging |
Het |
| Phf14 |
A |
T |
6: 11,933,340 (GRCm39) |
E67D |
unknown |
Het |
| Prdm16 |
C |
T |
4: 154,613,094 (GRCm39) |
G111D |
probably damaging |
Het |
| Ptpn23 |
G |
A |
9: 110,214,325 (GRCm39) |
T1692I |
unknown |
Het |
| Ptprb |
C |
T |
10: 116,204,671 (GRCm39) |
S1835L |
probably damaging |
Het |
| Rbm19 |
G |
A |
5: 120,254,532 (GRCm39) |
|
probably benign |
Het |
| Rgs7bp |
T |
A |
13: 105,119,382 (GRCm39) |
H152L |
possibly damaging |
Het |
| Rmdn3 |
A |
T |
2: 118,969,849 (GRCm39) |
L404Q |
probably damaging |
Het |
| Rock2 |
T |
A |
12: 17,023,144 (GRCm39) |
F1148I |
probably benign |
Het |
| Runx2 |
G |
A |
17: 45,125,079 (GRCm39) |
P80L |
probably damaging |
Het |
| Sec24c |
C |
A |
14: 20,739,401 (GRCm39) |
H559N |
probably damaging |
Het |
| Sephs2 |
T |
C |
7: 126,872,992 (GRCm39) |
S34G |
probably benign |
Het |
| Serpina6 |
A |
T |
12: 103,613,203 (GRCm39) |
S366T |
probably benign |
Het |
| Serpinb7 |
A |
T |
1: 107,378,052 (GRCm39) |
E248D |
probably benign |
Het |
| Sesn1 |
G |
T |
10: 41,779,724 (GRCm39) |
R386L |
possibly damaging |
Het |
| Skida1 |
T |
C |
2: 18,051,602 (GRCm39) |
S430G |
unknown |
Het |
| Slc28a2 |
A |
T |
2: 122,282,462 (GRCm39) |
|
probably null |
Het |
| Slc39a8 |
T |
C |
3: 135,563,299 (GRCm39) |
F203S |
possibly damaging |
Het |
| Svip |
A |
G |
7: 51,653,177 (GRCm39) |
S46P |
possibly damaging |
Het |
| Tbx21 |
T |
A |
11: 96,989,923 (GRCm39) |
D423V |
probably benign |
Het |
| Tcirg1 |
G |
A |
19: 3,953,576 (GRCm39) |
A117V |
probably null |
Het |
| Tmem63b |
T |
A |
17: 45,984,094 (GRCm39) |
K258N |
probably benign |
Het |
| Tmem94 |
A |
G |
11: 115,685,600 (GRCm39) |
N951S |
probably damaging |
Het |
| Uba2 |
G |
T |
7: 33,840,854 (GRCm39) |
D591E |
probably benign |
Het |
| Unc13b |
C |
T |
4: 43,258,893 (GRCm39) |
R1356W |
probably damaging |
Het |
| Wasf3 |
A |
G |
5: 146,403,615 (GRCm39) |
T242A |
probably benign |
Het |
| Wscd1 |
T |
C |
11: 71,650,709 (GRCm39) |
L12P |
probably damaging |
Het |
| Zfp770 |
T |
C |
2: 114,027,872 (GRCm39) |
K66E |
probably damaging |
Het |
| Zfyve26 |
A |
T |
12: 79,315,182 (GRCm39) |
D1431E |
probably benign |
Het |
| Zhx2 |
G |
A |
15: 57,686,746 (GRCm39) |
R705H |
probably benign |
Het |
|
| Other mutations in Prex1 |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL00161:Prex1
|
APN |
2 |
166,480,321 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL00309:Prex1
|
APN |
2 |
166,451,743 (GRCm39) |
missense |
probably damaging |
0.99 |
|
IGL00953:Prex1
|
APN |
2 |
166,480,329 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL00961:Prex1
|
APN |
2 |
166,427,656 (GRCm39) |
missense |
probably damaging |
0.98 |
|
IGL01300:Prex1
|
APN |
2 |
166,480,327 (GRCm39) |
missense |
possibly damaging |
0.46 |
|
IGL01318:Prex1
|
APN |
2 |
166,411,260 (GRCm39) |
splice site |
probably benign |
|
|
IGL01753:Prex1
|
APN |
2 |
166,444,802 (GRCm39) |
missense |
probably benign |
0.11 |
|
IGL01819:Prex1
|
APN |
2 |
166,463,165 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02058:Prex1
|
APN |
2 |
166,427,103 (GRCm39) |
missense |
probably benign |
0.00 |
|
IGL02251:Prex1
|
APN |
2 |
166,419,806 (GRCm39) |
missense |
probably damaging |
0.99 |
|
IGL02326:Prex1
|
APN |
2 |
166,463,105 (GRCm39) |
missense |
probably benign |
0.35 |
|
IGL02366:Prex1
|
APN |
2 |
166,422,347 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02414:Prex1
|
APN |
2 |
166,451,748 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02660:Prex1
|
APN |
2 |
166,435,787 (GRCm39) |
missense |
probably damaging |
0.97 |
|
IGL02666:Prex1
|
APN |
2 |
166,414,909 (GRCm39) |
missense |
probably benign |
0.00 |
|
IGL02874:Prex1
|
APN |
2 |
166,426,967 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02935:Prex1
|
APN |
2 |
166,412,265 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL03179:Prex1
|
APN |
2 |
166,427,114 (GRCm39) |
missense |
probably benign |
0.31 |
|
R0207:Prex1
|
UTSW |
2 |
166,427,818 (GRCm39) |
missense |
possibly damaging |
0.92 |
|
R0415:Prex1
|
UTSW |
2 |
166,428,619 (GRCm39) |
unclassified |
probably benign |
|
|
R0420:Prex1
|
UTSW |
2 |
166,431,491 (GRCm39) |
missense |
probably benign |
0.13 |
|
R0449:Prex1
|
UTSW |
2 |
166,411,297 (GRCm39) |
missense |
probably benign |
0.16 |
|
R0458:Prex1
|
UTSW |
2 |
166,427,743 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R0927:Prex1
|
UTSW |
2 |
166,428,457 (GRCm39) |
missense |
probably benign |
0.01 |
|
R1299:Prex1
|
UTSW |
2 |
166,427,827 (GRCm39) |
missense |
possibly damaging |
0.62 |
|
R1414:Prex1
|
UTSW |
2 |
166,435,781 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1440:Prex1
|
UTSW |
2 |
166,422,383 (GRCm39) |
missense |
probably damaging |
0.98 |
|
R1506:Prex1
|
UTSW |
2 |
166,429,001 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1725:Prex1
|
UTSW |
2 |
166,443,656 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1831:Prex1
|
UTSW |
2 |
166,427,021 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1883:Prex1
|
UTSW |
2 |
166,425,192 (GRCm39) |
missense |
probably benign |
0.20 |
|
R1896:Prex1
|
UTSW |
2 |
166,428,574 (GRCm39) |
missense |
probably benign |
0.01 |
|
R2022:Prex1
|
UTSW |
2 |
166,417,534 (GRCm39) |
missense |
possibly damaging |
0.80 |
|
R2091:Prex1
|
UTSW |
2 |
166,411,285 (GRCm39) |
missense |
possibly damaging |
0.95 |
|
R2258:Prex1
|
UTSW |
2 |
166,429,077 (GRCm39) |
missense |
probably benign |
0.00 |
|
R2263:Prex1
|
UTSW |
2 |
166,430,988 (GRCm39) |
splice site |
probably benign |
|
|
R2276:Prex1
|
UTSW |
2 |
166,419,875 (GRCm39) |
missense |
probably benign |
0.34 |
|
R2279:Prex1
|
UTSW |
2 |
166,419,875 (GRCm39) |
missense |
probably benign |
0.34 |
|
R2680:Prex1
|
UTSW |
2 |
166,443,692 (GRCm39) |
missense |
possibly damaging |
0.92 |
|
R3024:Prex1
|
UTSW |
2 |
166,430,956 (GRCm39) |
missense |
probably benign |
0.04 |
|
R3421:Prex1
|
UTSW |
2 |
166,459,774 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R3614:Prex1
|
UTSW |
2 |
166,451,701 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4244:Prex1
|
UTSW |
2 |
166,412,256 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4605:Prex1
|
UTSW |
2 |
166,555,464 (GRCm39) |
missense |
probably benign |
0.45 |
|
R4685:Prex1
|
UTSW |
2 |
166,480,252 (GRCm39) |
missense |
probably damaging |
0.97 |
|
R4787:Prex1
|
UTSW |
2 |
166,480,260 (GRCm39) |
missense |
probably benign |
0.01 |
|
R4796:Prex1
|
UTSW |
2 |
166,434,211 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4825:Prex1
|
UTSW |
2 |
166,427,777 (GRCm39) |
nonsense |
probably null |
|
|
R4955:Prex1
|
UTSW |
2 |
166,415,143 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R5046:Prex1
|
UTSW |
2 |
166,414,883 (GRCm39) |
missense |
probably benign |
0.00 |
|
R5095:Prex1
|
UTSW |
2 |
166,423,841 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5408:Prex1
|
UTSW |
2 |
166,417,573 (GRCm39) |
small insertion |
probably benign |
|
|
R5462:Prex1
|
UTSW |
2 |
166,486,728 (GRCm39) |
missense |
probably benign |
0.02 |
|
R5535:Prex1
|
UTSW |
2 |
166,422,193 (GRCm39) |
missense |
possibly damaging |
0.80 |
|
R5777:Prex1
|
UTSW |
2 |
166,428,579 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5813:Prex1
|
UTSW |
2 |
166,425,127 (GRCm39) |
missense |
probably benign |
|
|
R5860:Prex1
|
UTSW |
2 |
166,486,604 (GRCm39) |
intron |
probably benign |
|
|
R5984:Prex1
|
UTSW |
2 |
166,427,664 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6009:Prex1
|
UTSW |
2 |
166,423,904 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6174:Prex1
|
UTSW |
2 |
166,414,883 (GRCm39) |
missense |
probably benign |
0.00 |
|
R6345:Prex1
|
UTSW |
2 |
166,414,880 (GRCm39) |
missense |
probably null |
0.81 |
|
R6897:Prex1
|
UTSW |
2 |
166,423,913 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R6935:Prex1
|
UTSW |
2 |
166,441,575 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7025:Prex1
|
UTSW |
2 |
166,455,107 (GRCm39) |
small insertion |
probably benign |
|
|
R7037:Prex1
|
UTSW |
2 |
166,429,100 (GRCm39) |
missense |
probably benign |
0.05 |
|
R7076:Prex1
|
UTSW |
2 |
166,475,302 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R7361:Prex1
|
UTSW |
2 |
166,555,490 (GRCm39) |
missense |
probably benign |
0.04 |
|
R7381:Prex1
|
UTSW |
2 |
166,429,047 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7721:Prex1
|
UTSW |
2 |
166,419,810 (GRCm39) |
nonsense |
probably null |
|
|
R7763:Prex1
|
UTSW |
2 |
166,555,629 (GRCm39) |
missense |
unknown |
|
|
R7809:Prex1
|
UTSW |
2 |
166,415,164 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R7915:Prex1
|
UTSW |
2 |
166,463,112 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7971:Prex1
|
UTSW |
2 |
166,423,859 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7998:Prex1
|
UTSW |
2 |
166,428,965 (GRCm39) |
critical splice donor site |
probably null |
|
|
R8029:Prex1
|
UTSW |
2 |
166,417,523 (GRCm39) |
missense |
probably benign |
0.01 |
|
R8193:Prex1
|
UTSW |
2 |
166,435,780 (GRCm39) |
missense |
possibly damaging |
0.60 |
|
R8352:Prex1
|
UTSW |
2 |
166,431,493 (GRCm39) |
missense |
probably benign |
0.05 |
|
R8452:Prex1
|
UTSW |
2 |
166,431,493 (GRCm39) |
missense |
probably benign |
0.05 |
|
R8927:Prex1
|
UTSW |
2 |
166,426,995 (GRCm39) |
missense |
probably damaging |
0.97 |
|
R8928:Prex1
|
UTSW |
2 |
166,426,995 (GRCm39) |
missense |
probably damaging |
0.97 |
|
R9021:Prex1
|
UTSW |
2 |
166,432,429 (GRCm39) |
missense |
possibly damaging |
0.47 |
|
R9070:Prex1
|
UTSW |
2 |
166,427,707 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9213:Prex1
|
UTSW |
2 |
166,417,669 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R9511:Prex1
|
UTSW |
2 |
166,413,481 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9514:Prex1
|
UTSW |
2 |
166,419,896 (GRCm39) |
missense |
possibly damaging |
0.53 |
|
R9529:Prex1
|
UTSW |
2 |
166,431,518 (GRCm39) |
missense |
probably damaging |
1.00 |
|
X0065:Prex1
|
UTSW |
2 |
166,428,545 (GRCm39) |
missense |
probably benign |
|
|
Z1176:Prex1
|
UTSW |
2 |
166,414,890 (GRCm39) |
nonsense |
probably null |
|
|
Z1177:Prex1
|
UTSW |
2 |
166,434,148 (GRCm39) |
missense |
probably damaging |
0.98 |
|
| Predicted Primers |
PCR Primer
(F):5'- TTTCAGGGACAGGTAAGCCAAG -3'
(R):5'- TTAGAAGGATGTCAGTGGCG -3'
Sequencing Primer
(F):5'- CCCAGAGAACATGGGCACTG -3'
(R):5'- CAGTGGAGGTCTCAGGCTG -3'
|
| Posted On |
2019-06-26 |
Incidental Mutation