Incidental Mutation 'R6753:Fgfr3'
| ID |
530881 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Fgfr3
|
| Ensembl Gene |
ENSMUSG00000054252 |
| Gene Name |
fibroblast growth factor receptor 3 |
| Synonyms |
sam3, Fgfr-3, HBGFR |
| MMRRC Submission |
044870-MU
|
| Accession Numbers |
|
| Essential gene? |
Possibly non essential
(E-score: 0.349)
|
| Stock # |
R6753 (G1)
|
| Quality Score |
225.009 |
|
Status
|
Validated
|
| Chromosome |
5 |
| Chromosomal Location |
33721674-33737068 bp(+) (GRCm38) |
| Type of Mutation |
missense |
| DNA Base Change (assembly) |
T to C
at 33732159 bp (GRCm38)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
Serine to Proline
at position 301
(S301P)
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000143945
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000067150]
[ENSMUST00000087820]
[ENSMUST00000114411]
[ENSMUST00000155002]
[ENSMUST00000164207]
[ENSMUST00000169212]
[ENSMUST00000171509]
[ENSMUST00000202138]
[ENSMUST00000201295]
[ENSMUST00000201437]
|
| AlphaFold |
no structure available at present |
| Predicted Effect |
probably benign
Transcript: ENSMUST00000067150
AA Change: S319P
PolyPhen 2
Score 0.223 (Sensitivity: 0.91; Specificity: 0.88)
|
| SMART Domains |
Protein: ENSMUSP00000070998
Gene: ENSMUSG00000054252
AA Change: S319P
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
low complexity region
|
125 |
144 |
N/A |
INTRINSIC |
|
IGc2
|
161 |
229 |
1.2e-15 |
SMART |
|
IGc2
|
260 |
340 |
3.28e-8 |
SMART |
|
transmembrane domain
|
367 |
389 |
N/A |
INTRINSIC |
|
TyrKc
|
466 |
742 |
3.14e-153 |
SMART |
|
low complexity region
|
765 |
781 |
N/A |
INTRINSIC |
|
low complexity region
|
789 |
798 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000087820
AA Change: S301P
PolyPhen 2
Score 0.349 (Sensitivity: 0.90; Specificity: 0.89)
|
| SMART Domains |
Protein: ENSMUSP00000085122
Gene: ENSMUSG00000054252
AA Change: S301P
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
IGc2
|
143 |
211 |
1.2e-15 |
SMART |
|
IGc2
|
242 |
322 |
3.28e-8 |
SMART |
|
transmembrane domain
|
349 |
371 |
N/A |
INTRINSIC |
|
TyrKc
|
448 |
724 |
3.14e-153 |
SMART |
|
low complexity region
|
747 |
763 |
N/A |
INTRINSIC |
|
low complexity region
|
771 |
780 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000114411
|
| SMART Domains |
Protein: ENSMUSP00000110053
Gene: ENSMUSG00000054252
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
low complexity region
|
125 |
144 |
N/A |
INTRINSIC |
|
IGc2
|
161 |
229 |
1.2e-15 |
SMART |
|
IGc2
|
260 |
339 |
2.77e-6 |
SMART |
|
transmembrane domain
|
369 |
391 |
N/A |
INTRINSIC |
|
TyrKc
|
468 |
744 |
3.14e-153 |
SMART |
|
low complexity region
|
767 |
783 |
N/A |
INTRINSIC |
|
low complexity region
|
791 |
800 |
N/A |
INTRINSIC |
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000132724
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000134610
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000142860
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000152661
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000155002
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000164207
AA Change: S319P
PolyPhen 2
Score 0.223 (Sensitivity: 0.91; Specificity: 0.88)
|
| SMART Domains |
Protein: ENSMUSP00000133064
Gene: ENSMUSG00000054252
AA Change: S319P
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
low complexity region
|
125 |
144 |
N/A |
INTRINSIC |
|
IGc2
|
161 |
229 |
1.2e-15 |
SMART |
|
IGc2
|
260 |
340 |
3.28e-8 |
SMART |
|
transmembrane domain
|
367 |
389 |
N/A |
INTRINSIC |
|
TyrKc
|
467 |
743 |
3.14e-153 |
SMART |
|
low complexity region
|
766 |
782 |
N/A |
INTRINSIC |
|
low complexity region
|
790 |
799 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000169212
AA Change: S319P
PolyPhen 2
Score 0.223 (Sensitivity: 0.91; Specificity: 0.88)
|
| SMART Domains |
Protein: ENSMUSP00000130856
Gene: ENSMUSG00000054252
AA Change: S319P
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
low complexity region
|
125 |
144 |
N/A |
INTRINSIC |
|
IGc2
|
161 |
229 |
1.2e-15 |
SMART |
|
IGc2
|
260 |
340 |
3.28e-8 |
SMART |
|
transmembrane domain
|
367 |
389 |
N/A |
INTRINSIC |
|
TyrKc
|
466 |
742 |
3.14e-153 |
SMART |
|
low complexity region
|
765 |
781 |
N/A |
INTRINSIC |
|
low complexity region
|
789 |
798 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000171509
|
| SMART Domains |
Protein: ENSMUSP00000131845
Gene: ENSMUSG00000054252
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
low complexity region
|
125 |
144 |
N/A |
INTRINSIC |
|
IGc2
|
161 |
229 |
1.2e-15 |
SMART |
|
IGc2
|
260 |
339 |
2.77e-6 |
SMART |
|
transmembrane domain
|
369 |
391 |
N/A |
INTRINSIC |
|
TyrKc
|
468 |
744 |
3.14e-153 |
SMART |
|
low complexity region
|
767 |
783 |
N/A |
INTRINSIC |
|
low complexity region
|
791 |
800 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000202138
AA Change: S301P
PolyPhen 2
Score 0.349 (Sensitivity: 0.90; Specificity: 0.89)
|
| SMART Domains |
Protein: ENSMUSP00000143945
Gene: ENSMUSG00000054252
AA Change: S301P
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
5.01e-4 |
SMART |
|
IGc2
|
143 |
211 |
1.2e-15 |
SMART |
|
IGc2
|
242 |
322 |
3.28e-8 |
SMART |
|
transmembrane domain
|
349 |
371 |
N/A |
INTRINSIC |
|
TyrKc
|
448 |
724 |
3.14e-153 |
SMART |
|
low complexity region
|
747 |
763 |
N/A |
INTRINSIC |
|
low complexity region
|
771 |
780 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000181298
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000201295
|
| SMART Domains |
Protein: ENSMUSP00000144104
Gene: ENSMUSG00000054252
| Domain | Start | End | E-Value | Type |
|---|
|
IG
|
11 |
71 |
1.9e-3 |
SMART |
|
transmembrane domain
|
90 |
112 |
N/A |
INTRINSIC |
|
PDB:2PSQ|B
|
126 |
223 |
2e-30 |
PDB |
|
Blast:IG_like
|
140 |
223 |
2e-51 |
BLAST |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000202791
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000201437
|
| SMART Domains |
Protein: ENSMUSP00000144379
Gene: ENSMUSG00000054252
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
20 |
N/A |
INTRINSIC |
|
IGc2
|
50 |
114 |
2e-6 |
SMART |
|
Pfam:Ig_3
|
144 |
194 |
2.1e-3 |
PFAM |
|
Pfam:I-set
|
153 |
194 |
9.2e-6 |
PFAM |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000202182
|
| Meta Mutation Damage Score |
0.0905 |
| Coding Region Coverage |
- 1x: 99.9%
- 3x: 99.6%
- 10x: 98.3%
- 20x: 95.1%
|
| Validation Efficiency |
99% (68/69) |
| MGI Phenotype |
FUNCTION: This gene encodes a member of the fibroblast growth factor receptor family. Members of this family are highly conserved proteins that differ from one another in their ligand affinities and tissue distribution. A representative protein consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene may be associated with craniosynostosis and multiple types of skeletal dysplasia. A pseudogene of this gene is located on chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2011]
PHENOTYPE: Mutant alleles generally cause skeletal deformities, with some causing decreased body size, premature death, or hearing loss due to developmental defects of the ear. [provided by MGI curators]
|
| Allele List at MGI |
|
| Other mutations in this stock |
Total: 64 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Aatk |
G |
A |
11: 120,010,151 (GRCm38) |
P1083S |
probably benign |
Het |
| Abcb5 |
T |
A |
12: 118,944,906 (GRCm38) |
N101I |
possibly damaging |
Het |
| Adrb2 |
A |
G |
18: 62,179,553 (GRCm38) |
V67A |
possibly damaging |
Het |
| Agk |
T |
A |
6: 40,368,570 (GRCm38) |
|
probably null |
Het |
| Akap10 |
A |
T |
11: 61,886,777 (GRCm38) |
M586K |
probably damaging |
Het |
| Akt3 |
A |
T |
1: 177,050,190 (GRCm38) |
Y337* |
probably null |
Het |
| Armc1 |
A |
G |
3: 19,144,398 (GRCm38) |
F133L |
possibly damaging |
Het |
| Bank1 |
T |
C |
3: 136,093,308 (GRCm38) |
E424G |
probably damaging |
Het |
| Cacna1a |
A |
G |
8: 84,580,205 (GRCm38) |
E1363G |
probably damaging |
Het |
| Cacna1d |
C |
A |
14: 30,042,786 (GRCm38) |
A2076S |
probably damaging |
Het |
| Ccdc73 |
T |
A |
2: 104,991,524 (GRCm38) |
L606* |
probably null |
Het |
| Ccdc8 |
C |
T |
7: 16,996,637 (GRCm38) |
Q684* |
probably null |
Het |
| Ces1b |
T |
A |
8: 93,067,020 (GRCm38) |
K314* |
probably null |
Het |
| Ces1e |
T |
A |
8: 93,215,128 (GRCm38) |
N238I |
probably damaging |
Het |
| Chd4 |
A |
G |
6: 125,114,300 (GRCm38) |
N1238S |
probably benign |
Het |
| Cmtr2 |
T |
A |
8: 110,222,979 (GRCm38) |
D640E |
probably damaging |
Het |
| Col7a1 |
C |
T |
9: 108,958,128 (GRCm38) |
T559I |
unknown |
Het |
| Comt |
T |
C |
16: 18,408,021 (GRCm38) |
K205R |
probably benign |
Het |
| Dbp |
A |
T |
7: 45,708,404 (GRCm38) |
E232V |
probably damaging |
Het |
| Dcbld2 |
A |
G |
16: 58,456,130 (GRCm38) |
T470A |
possibly damaging |
Het |
| Eml6 |
T |
A |
11: 29,754,987 (GRCm38) |
D1519V |
probably damaging |
Het |
| Evpl |
T |
A |
11: 116,237,906 (GRCm38) |
H31L |
possibly damaging |
Het |
| Exoc1 |
T |
A |
5: 76,563,339 (GRCm38) |
I86N |
probably damaging |
Het |
| Fat3 |
C |
T |
9: 15,915,061 (GRCm38) |
E4532K |
possibly damaging |
Het |
| Gas2l1 |
C |
T |
11: 5,064,254 (GRCm38) |
V69I |
probably damaging |
Het |
| Gm2042 |
T |
A |
12: 87,958,084 (GRCm38) |
I107K |
probably damaging |
Het |
| Gucy1b1 |
T |
C |
3: 82,039,747 (GRCm38) |
D385G |
probably null |
Het |
| Ints1 |
T |
A |
5: 139,765,175 (GRCm38) |
E824D |
probably damaging |
Het |
| Itfg1 |
T |
C |
8: 85,835,078 (GRCm38) |
D142G |
probably benign |
Het |
| Jaml |
A |
G |
9: 45,107,379 (GRCm38) |
N359D |
probably benign |
Het |
| Kcnh7 |
T |
A |
2: 62,850,377 (GRCm38) |
I289L |
probably benign |
Het |
| Klf12 |
G |
A |
14: 100,109,776 (GRCm38) |
Q40* |
probably null |
Het |
| Mcm4 |
A |
C |
16: 15,629,362 (GRCm38) |
N579K |
possibly damaging |
Het |
| Mfsd2b |
A |
T |
12: 4,867,358 (GRCm38) |
F179I |
possibly damaging |
Het |
| Mmp11 |
C |
T |
10: 75,928,374 (GRCm38) |
V86M |
probably damaging |
Het |
| Mogs |
T |
C |
6: 83,115,882 (GRCm38) |
V101A |
probably damaging |
Het |
| Narf |
T |
A |
11: 121,242,626 (GRCm38) |
H84Q |
probably benign |
Het |
| Olfr987 |
C |
A |
2: 85,331,798 (GRCm38) |
M33I |
probably benign |
Het |
| Otog |
A |
C |
7: 46,249,071 (GRCm38) |
E204D |
probably benign |
Het |
| Parp8 |
G |
A |
13: 116,895,115 (GRCm38) |
H354Y |
possibly damaging |
Het |
| Pcnx |
C |
A |
12: 81,964,480 (GRCm38) |
D1238E |
probably damaging |
Het |
| Pi4ka |
A |
G |
16: 17,376,982 (GRCm38) |
L184P |
possibly damaging |
Het |
| Pkd1l3 |
C |
T |
8: 109,624,449 (GRCm38) |
T642I |
probably damaging |
Het |
| Pkhd1l1 |
G |
A |
15: 44,589,663 (GRCm38) |
E3995K |
probably benign |
Het |
| Prdm9 |
A |
T |
17: 15,544,956 (GRCm38) |
Y521N |
probably benign |
Het |
| Prex2 |
A |
G |
1: 11,184,456 (GRCm38) |
S1105G |
probably damaging |
Het |
| Prss35 |
T |
A |
9: 86,756,100 (GRCm38) |
F308I |
probably damaging |
Het |
| Rab22a |
C |
T |
2: 173,701,055 (GRCm38) |
A167V |
probably benign |
Het |
| Rims2 |
A |
G |
15: 39,566,973 (GRCm38) |
Q871R |
possibly damaging |
Het |
| Rorb |
A |
T |
19: 18,957,247 (GRCm38) |
M253K |
probably benign |
Het |
| Ryr3 |
T |
C |
2: 112,652,610 (GRCm38) |
D4269G |
probably damaging |
Het |
| Snx11 |
T |
C |
11: 96,769,906 (GRCm38) |
|
probably benign |
Het |
| Son |
A |
G |
16: 91,657,188 (GRCm38) |
Q941R |
probably damaging |
Het |
| Sptbn2 |
G |
T |
19: 4,747,785 (GRCm38) |
R1880L |
probably benign |
Het |
| Sun1 |
G |
A |
5: 139,215,259 (GRCm38) |
|
probably null |
Het |
| Tprn |
A |
G |
2: 25,264,038 (GRCm38) |
R451G |
probably benign |
Het |
| Trbv30 |
T |
A |
6: 41,281,377 (GRCm38) |
M1K |
probably null |
Het |
| Ttn |
C |
A |
2: 76,738,221 (GRCm38) |
G25697W |
probably damaging |
Het |
| Ubb |
T |
G |
11: 62,551,527 (GRCm38) |
|
probably null |
Het |
| Unc13b |
C |
T |
4: 43,239,331 (GRCm38) |
R1038C |
probably damaging |
Het |
| Usp7 |
T |
C |
16: 8,696,911 (GRCm38) |
M687V |
probably benign |
Het |
| Zfp160 |
G |
A |
17: 21,020,734 (GRCm38) |
M21I |
probably benign |
Het |
| Zfp868 |
T |
C |
8: 69,612,096 (GRCm38) |
N196S |
probably benign |
Het |
| Zufsp |
A |
T |
10: 33,928,029 (GRCm38) |
I483N |
probably damaging |
Het |
|
| Other mutations in Fgfr3 |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL00705:Fgfr3
|
APN |
5 |
33,735,140 (GRCm38) |
missense |
possibly damaging |
0.57 |
|
IGL01585:Fgfr3
|
APN |
5 |
33,733,961 (GRCm38) |
missense |
probably damaging |
0.96 |
|
IGL03266:Fgfr3
|
APN |
5 |
33,734,365 (GRCm38) |
missense |
probably damaging |
1.00 |
|
IGL03285:Fgfr3
|
APN |
5 |
33,735,213 (GRCm38) |
missense |
probably damaging |
1.00 |
|
PIT4280001:Fgfr3
|
UTSW |
5 |
33,732,232 (GRCm38) |
missense |
probably benign |
0.13 |
|
R0543:Fgfr3
|
UTSW |
5 |
33,729,710 (GRCm38) |
start codon destroyed |
probably null |
0.00 |
|
R0604:Fgfr3
|
UTSW |
5 |
33,732,782 (GRCm38) |
missense |
probably damaging |
0.99 |
|
R1496:Fgfr3
|
UTSW |
5 |
33,729,750 (GRCm38) |
missense |
probably damaging |
0.96 |
|
R1861:Fgfr3
|
UTSW |
5 |
33,729,746 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R2919:Fgfr3
|
UTSW |
5 |
33,733,940 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R2920:Fgfr3
|
UTSW |
5 |
33,733,940 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R4361:Fgfr3
|
UTSW |
5 |
33,723,332 (GRCm38) |
intron |
probably benign |
|
|
R4506:Fgfr3
|
UTSW |
5 |
33,729,999 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R4513:Fgfr3
|
UTSW |
5 |
33,723,116 (GRCm38) |
intron |
probably benign |
|
|
R4647:Fgfr3
|
UTSW |
5 |
33,734,986 (GRCm38) |
unclassified |
probably benign |
|
|
R5240:Fgfr3
|
UTSW |
5 |
33,730,038 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R5251:Fgfr3
|
UTSW |
5 |
33,735,556 (GRCm38) |
unclassified |
probably benign |
|
|
R5454:Fgfr3
|
UTSW |
5 |
33,723,298 (GRCm38) |
intron |
probably benign |
|
|
R5595:Fgfr3
|
UTSW |
5 |
33,730,003 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R5984:Fgfr3
|
UTSW |
5 |
33,729,705 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R6985:Fgfr3
|
UTSW |
5 |
33,735,441 (GRCm38) |
missense |
probably null |
1.00 |
|
R7106:Fgfr3
|
UTSW |
5 |
33,731,414 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R7221:Fgfr3
|
UTSW |
5 |
33,732,748 (GRCm38) |
frame shift |
probably null |
|
|
R7319:Fgfr3
|
UTSW |
5 |
33,727,802 (GRCm38) |
missense |
possibly damaging |
0.88 |
|
R7373:Fgfr3
|
UTSW |
5 |
33,727,690 (GRCm38) |
missense |
probably benign |
0.00 |
|
R7497:Fgfr3
|
UTSW |
5 |
33,735,422 (GRCm38) |
frame shift |
probably null |
|
|
R7498:Fgfr3
|
UTSW |
5 |
33,735,422 (GRCm38) |
frame shift |
probably null |
|
|
R7499:Fgfr3
|
UTSW |
5 |
33,735,422 (GRCm38) |
frame shift |
probably null |
|
|
R7883:Fgfr3
|
UTSW |
5 |
33,733,891 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R8129:Fgfr3
|
UTSW |
5 |
33,733,906 (GRCm38) |
missense |
probably damaging |
0.98 |
|
R8179:Fgfr3
|
UTSW |
5 |
33,727,755 (GRCm38) |
missense |
probably benign |
0.00 |
|
R8422:Fgfr3
|
UTSW |
5 |
33,734,905 (GRCm38) |
nonsense |
probably null |
|
|
R8935:Fgfr3
|
UTSW |
5 |
33,735,466 (GRCm38) |
missense |
probably damaging |
1.00 |
|
R9179:Fgfr3
|
UTSW |
5 |
33,729,972 (GRCm38) |
missense |
possibly damaging |
0.78 |
|
R9368:Fgfr3
|
UTSW |
5 |
33,727,872 (GRCm38) |
missense |
probably benign |
|
|
R9414:Fgfr3
|
UTSW |
5 |
33,729,954 (GRCm38) |
missense |
possibly damaging |
0.81 |
|
R9689:Fgfr3
|
UTSW |
5 |
33,734,904 (GRCm38) |
missense |
probably damaging |
0.99 |
|
| Predicted Primers |
PCR Primer
(F):5'- TTGCTCACCTTGGGACAGAG -3'
(R):5'- AGCTTTGGCATGTCCTGAGAC -3'
Sequencing Primer
(F):5'- TCACCTTGGGACAGAGGACTC -3'
(R):5'- GTCCTGAGACAGCACCCTAAGAG -3'
|
| Posted On |
2018-08-01 |
Incidental Mutation