Incidental Mutation 'PIT4445001:Atp8a1'
| ID |
555389 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Atp8a1
|
| Ensembl Gene |
ENSMUSG00000037685 |
| Gene Name |
ATPase phospholipid transporting 8A1 |
| Synonyms |
Atp3a2, B230107D19Rik |
| Accession Numbers |
|
| Essential gene? |
Non essential
(E-score: 0.000)
|
| Stock # |
PIT4445001 (G1)
|
| Quality Score |
149.008 |
|
Status
|
Not validated
|
| Chromosome |
5 |
| Chromosomal Location |
67775483-68004777 bp(-) (GRCm39) |
| Type of Mutation |
missense |
| DNA Base Change (assembly) |
A to G
at 67780003 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
Valine to Alanine
at position 1145
(V1145A)
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000042215
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000037380]
[ENSMUST00000072971]
[ENSMUST00000135930]
[ENSMUST00000142843]
[ENSMUST00000200955]
|
| AlphaFold |
P70704 |
| Predicted Effect |
|
| SMART Domains |
Protein: ENSMUSP00000042215
Gene: ENSMUSG00000037685
AA Change: V1145A
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:PhoLip_ATPase_N
|
38 |
101 |
9.8e-27 |
PFAM |
|
Pfam:E1-E2_ATPase
|
106 |
371 |
3e-11 |
PFAM |
|
Pfam:HAD
|
406 |
810 |
3.8e-23 |
PFAM |
|
Pfam:Cation_ATPase
|
485 |
585 |
6e-14 |
PFAM |
|
Pfam:PhoLip_ATPase_C
|
827 |
1079 |
8.2e-82 |
PFAM |
|
| Predicted Effect |
possibly damaging
Transcript: ENSMUST00000072971
AA Change: V1145A
PolyPhen 2
Score 0.899 (Sensitivity: 0.82; Specificity: 0.94)
|
| SMART Domains |
Protein: ENSMUSP00000072738
Gene: ENSMUSG00000037685
AA Change: V1145A
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:E1-E2_ATPase
|
104 |
375 |
2.1e-22 |
PFAM |
|
Pfam:Hydrolase
|
403 |
798 |
2.2e-14 |
PFAM |
|
Pfam:HAD
|
406 |
795 |
3e-18 |
PFAM |
|
Pfam:Hydrolase_like2
|
470 |
570 |
4.5e-14 |
PFAM |
|
| Predicted Effect |
probably damaging
Transcript: ENSMUST00000135930
AA Change: V1130A
PolyPhen 2
Score 0.987 (Sensitivity: 0.73; Specificity: 0.96)
|
| SMART Domains |
Protein: ENSMUSP00000118379
Gene: ENSMUSG00000037685
AA Change: V1130A
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:PhoLip_ATPase_N
|
38 |
101 |
1.1e-26 |
PFAM |
|
Pfam:E1-E2_ATPase
|
106 |
371 |
8.6e-14 |
PFAM |
|
Pfam:HAD
|
406 |
795 |
3.6e-23 |
PFAM |
|
Pfam:Cation_ATPase
|
470 |
570 |
1.2e-13 |
PFAM |
|
Pfam:PhoLip_ATPase_C
|
812 |
1064 |
8.4e-82 |
PFAM |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000142843
|
| SMART Domains |
Protein: ENSMUSP00000138599
Gene: ENSMUSG00000050010
| Domain | Start | End | E-Value | Type |
|---|
|
signal peptide
|
1 |
21 |
N/A |
INTRINSIC |
|
Pfam:Shisa
|
23 |
100 |
2.6e-24 |
PFAM |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000200955
|
| SMART Domains |
Protein: ENSMUSP00000144465
Gene: ENSMUSG00000037685
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:PhoLip_ATPase_N
|
38 |
101 |
7.5e-25 |
PFAM |
|
Pfam:E1-E2_ATPase
|
106 |
371 |
3.7e-13 |
PFAM |
|
| Coding Region Coverage |
- 1x: 93.5%
- 3x: 90.8%
- 10x: 84.5%
- 20x: 70.9%
|
| Validation Efficiency |
|
| MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The P-type adenosinetriphosphatases (P-type ATPases) are a family of proteins which use the free energy of ATP hydrolysis to drive uphill transport of ions across membranes. Several subfamilies of P-type ATPases have been identified. One subfamily catalyzes transport of heavy metal ions. Another subfamily transports non-heavy metal ions (NMHI). The protein encoded by this gene is a member of the third subfamily of P-type ATPases and acts to transport amphipaths, such as phosphatidylserine. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygous mutant mice are viable, fertile and phenotypically normal. [provided by MGI curators]
|
| Allele List at MGI |
|
| Other mutations in this stock |
Total: 73 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Abca8a |
T |
C |
11: 109,966,377 (GRCm39) |
K419E |
probably damaging |
Het |
| Adam7 |
T |
A |
14: 68,747,197 (GRCm39) |
K587N |
possibly damaging |
Het |
| Agl |
T |
C |
3: 116,565,109 (GRCm39) |
M382V |
|
Het |
| Agpat3 |
A |
T |
10: 78,109,927 (GRCm39) |
F341I |
possibly damaging |
Het |
| Ampd2 |
A |
T |
3: 107,982,328 (GRCm39) |
L767Q |
probably damaging |
Het |
| Arhgap28 |
A |
T |
17: 68,203,230 (GRCm39) |
D124E |
possibly damaging |
Het |
| Arhgap32 |
T |
C |
9: 32,172,152 (GRCm39) |
L1644P |
probably damaging |
Het |
| Asic4 |
T |
C |
1: 75,427,771 (GRCm39) |
V99A |
probably benign |
Het |
| Asns |
T |
A |
6: 7,689,277 (GRCm39) |
N75I |
probably damaging |
Het |
| Atp10a |
A |
G |
7: 58,453,215 (GRCm39) |
D798G |
probably damaging |
Het |
| Ccdc171 |
A |
G |
4: 83,579,984 (GRCm39) |
Q577R |
probably damaging |
Het |
| Cd247 |
T |
A |
1: 165,688,605 (GRCm39) |
D154E |
probably damaging |
Het |
| Ceacam1 |
A |
T |
7: 25,175,881 (GRCm39) |
N104K |
probably damaging |
Het |
| Chfr |
A |
G |
5: 110,299,543 (GRCm39) |
D312G |
possibly damaging |
Het |
| Ddb1 |
C |
A |
19: 10,603,334 (GRCm39) |
L881I |
probably damaging |
Het |
| Dgkh |
A |
T |
14: 78,813,382 (GRCm39) |
I1032N |
possibly damaging |
Het |
| Efcab6 |
A |
T |
15: 83,788,468 (GRCm39) |
V942D |
probably benign |
Het |
| Fmo5 |
A |
G |
3: 97,558,844 (GRCm39) |
T435A |
probably benign |
Het |
| Fpr1 |
T |
C |
17: 18,097,155 (GRCm39) |
Q278R |
probably benign |
Het |
| Fzr1 |
C |
T |
10: 81,205,228 (GRCm39) |
W256* |
probably null |
Het |
| Gabrb1 |
T |
C |
5: 72,266,125 (GRCm39) |
S261P |
probably damaging |
Het |
| Galr2 |
G |
T |
11: 116,172,474 (GRCm39) |
A55S |
probably benign |
Het |
| Gbp2 |
A |
T |
3: 142,343,227 (GRCm39) |
K581N |
probably benign |
Het |
| Gria1 |
A |
T |
11: 57,076,664 (GRCm39) |
Y89F |
probably damaging |
Het |
| Ibsp |
T |
A |
5: 104,450,170 (GRCm39) |
I26N |
possibly damaging |
Het |
| Igf1r |
T |
C |
7: 67,857,211 (GRCm39) |
F1058L |
probably damaging |
Het |
| Ighv1-16 |
A |
C |
12: 114,629,680 (GRCm39) |
C36G |
probably benign |
Het |
| Igll1 |
T |
C |
16: 16,678,783 (GRCm39) |
T176A |
probably benign |
Het |
| Ilkap |
T |
C |
1: 91,313,067 (GRCm39) |
T143A |
probably benign |
Het |
| Kdm3b |
A |
T |
18: 34,926,168 (GRCm39) |
K103* |
probably null |
Het |
| Mphosph9 |
A |
G |
5: 124,436,853 (GRCm39) |
I497T |
possibly damaging |
Het |
| Mrgpra3 |
G |
A |
7: 47,239,908 (GRCm39) |
T6I |
possibly damaging |
Het |
| Mrpl38 |
T |
C |
11: 116,023,384 (GRCm39) |
|
probably null |
Het |
| Myo3a |
A |
T |
2: 22,434,457 (GRCm39) |
E813V |
possibly damaging |
Het |
| Myo7b |
G |
T |
18: 32,092,519 (GRCm39) |
Q2093K |
possibly damaging |
Het |
| Myo7b |
T |
C |
18: 32,095,405 (GRCm39) |
K1851R |
probably damaging |
Het |
| P3h2 |
T |
A |
16: 25,803,749 (GRCm39) |
D339V |
probably benign |
Het |
| Pcdhb6 |
C |
A |
18: 37,468,300 (GRCm39) |
P407Q |
possibly damaging |
Het |
| Plch2 |
C |
A |
4: 155,093,483 (GRCm39) |
R153L |
probably damaging |
Het |
| Plppr4 |
G |
A |
3: 117,153,957 (GRCm39) |
|
probably benign |
Het |
| Ppp1r3a |
A |
G |
6: 14,717,776 (GRCm39) |
F1046S |
probably damaging |
Het |
| Pramel41 |
T |
G |
5: 94,596,366 (GRCm39) |
W468G |
probably benign |
Het |
| Prkacb |
A |
T |
3: 146,461,446 (GRCm39) |
L107M |
probably benign |
Het |
| Ranbp17 |
A |
G |
11: 33,431,020 (GRCm39) |
|
probably null |
Het |
| Rasl11b |
C |
A |
5: 74,357,994 (GRCm39) |
P88Q |
probably damaging |
Het |
| Rcc2 |
A |
G |
4: 140,448,460 (GRCm39) |
E503G |
possibly damaging |
Het |
| Rnf216 |
T |
A |
5: 143,071,758 (GRCm39) |
K407N |
probably damaging |
Het |
| Rusf1 |
A |
G |
7: 127,875,706 (GRCm39) |
V243A |
probably benign |
Het |
| Scrn3 |
G |
A |
2: 73,148,673 (GRCm39) |
M81I |
possibly damaging |
Het |
| Scube2 |
T |
C |
7: 109,408,387 (GRCm39) |
T687A |
probably benign |
Het |
| Serpinb10 |
T |
A |
1: 107,463,728 (GRCm39) |
F3L |
probably benign |
Het |
| Sgcb |
C |
T |
5: 73,797,155 (GRCm39) |
V202I |
probably damaging |
Het |
| Sgce |
A |
G |
6: 4,689,654 (GRCm39) |
V429A |
possibly damaging |
Het |
| Sh3rf2 |
T |
C |
18: 42,286,229 (GRCm39) |
V574A |
probably benign |
Het |
| Sncaip |
T |
C |
18: 53,002,016 (GRCm39) |
L179S |
probably damaging |
Het |
| Sntg2 |
A |
T |
12: 30,362,571 (GRCm39) |
D58E |
probably damaging |
Het |
| Taar3 |
T |
C |
10: 23,825,586 (GRCm39) |
I44T |
possibly damaging |
Het |
| Tmem87b |
G |
A |
2: 128,673,391 (GRCm39) |
V227I |
probably benign |
Het |
| Tnfsf9 |
T |
C |
17: 57,412,517 (GRCm39) |
L29P |
possibly damaging |
Het |
| Tnip2 |
T |
C |
5: 34,654,215 (GRCm39) |
H391R |
probably benign |
Het |
| Traf5 |
A |
G |
1: 191,729,768 (GRCm39) |
Y125H |
|
Het |
| Ttc23 |
T |
G |
7: 67,316,961 (GRCm39) |
I77M |
probably damaging |
Het |
| Ube2l3 |
T |
C |
16: 16,978,036 (GRCm39) |
N43S |
probably benign |
Het |
| Vars2 |
A |
T |
17: 35,977,103 (GRCm39) |
C142* |
probably null |
Het |
| Vmn2r15 |
A |
C |
5: 109,435,008 (GRCm39) |
D565E |
probably damaging |
Het |
| Vmn2r56 |
C |
T |
7: 12,449,153 (GRCm39) |
|
probably null |
Het |
| Vmn2r79 |
A |
T |
7: 86,651,408 (GRCm39) |
D269V |
possibly damaging |
Het |
| Vmn2r85 |
A |
T |
10: 130,261,572 (GRCm39) |
M255K |
probably benign |
Het |
| Wfdc6a |
T |
A |
2: 164,421,746 (GRCm39) |
*137C |
probably null |
Het |
| Wipi2 |
T |
C |
5: 142,652,639 (GRCm39) |
V417A |
probably benign |
Het |
| Xirp2 |
G |
T |
2: 67,340,116 (GRCm39) |
V786L |
possibly damaging |
Het |
| Zdhhc13 |
G |
A |
7: 48,445,697 (GRCm39) |
G26S |
probably benign |
Het |
| Zscan25 |
T |
A |
5: 145,227,422 (GRCm39) |
V362D |
probably damaging |
Het |
|
| Other mutations in Atp8a1 |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL00776:Atp8a1
|
APN |
5 |
67,906,486 (GRCm39) |
missense |
probably benign |
0.20 |
|
IGL00778:Atp8a1
|
APN |
5 |
67,817,246 (GRCm39) |
missense |
possibly damaging |
0.58 |
|
IGL01068:Atp8a1
|
APN |
5 |
67,824,680 (GRCm39) |
missense |
probably benign |
0.02 |
|
IGL01152:Atp8a1
|
APN |
5 |
68,004,549 (GRCm39) |
missense |
probably damaging |
0.99 |
|
IGL01572:Atp8a1
|
APN |
5 |
67,824,994 (GRCm39) |
missense |
probably benign |
|
|
IGL01608:Atp8a1
|
APN |
5 |
67,970,479 (GRCm39) |
nonsense |
probably null |
|
|
IGL02171:Atp8a1
|
APN |
5 |
67,895,808 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02330:Atp8a1
|
APN |
5 |
67,970,520 (GRCm39) |
missense |
probably damaging |
0.98 |
|
IGL02381:Atp8a1
|
APN |
5 |
67,863,338 (GRCm39) |
missense |
probably benign |
|
|
IGL02420:Atp8a1
|
APN |
5 |
67,840,126 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL02440:Atp8a1
|
APN |
5 |
67,824,777 (GRCm39) |
splice site |
probably benign |
|
|
IGL02598:Atp8a1
|
APN |
5 |
67,840,099 (GRCm39) |
critical splice donor site |
probably null |
|
|
IGL03259:Atp8a1
|
APN |
5 |
67,781,349 (GRCm39) |
splice site |
probably null |
|
|
IGL03336:Atp8a1
|
APN |
5 |
67,887,150 (GRCm39) |
nonsense |
probably null |
|
|
IGL03380:Atp8a1
|
APN |
5 |
67,889,529 (GRCm39) |
missense |
probably benign |
0.25 |
|
PIT4131001:Atp8a1
|
UTSW |
5 |
67,779,945 (GRCm39) |
nonsense |
probably null |
|
|
R0208:Atp8a1
|
UTSW |
5 |
67,932,064 (GRCm39) |
critical splice donor site |
probably null |
|
|
R0276:Atp8a1
|
UTSW |
5 |
67,944,016 (GRCm39) |
splice site |
probably benign |
|
|
R0279:Atp8a1
|
UTSW |
5 |
67,970,435 (GRCm39) |
splice site |
probably null |
|
|
R0329:Atp8a1
|
UTSW |
5 |
67,969,416 (GRCm39) |
splice site |
probably benign |
|
|
R0603:Atp8a1
|
UTSW |
5 |
67,914,039 (GRCm39) |
critical splice acceptor site |
probably null |
|
|
R0715:Atp8a1
|
UTSW |
5 |
67,932,068 (GRCm39) |
missense |
probably benign |
0.00 |
|
R0763:Atp8a1
|
UTSW |
5 |
67,817,226 (GRCm39) |
missense |
probably benign |
|
|
R1296:Atp8a1
|
UTSW |
5 |
67,780,049 (GRCm39) |
splice site |
probably benign |
|
|
R1631:Atp8a1
|
UTSW |
5 |
67,906,395 (GRCm39) |
splice site |
probably null |
|
|
R1764:Atp8a1
|
UTSW |
5 |
67,788,910 (GRCm39) |
missense |
probably benign |
0.14 |
|
R1771:Atp8a1
|
UTSW |
5 |
67,805,074 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1885:Atp8a1
|
UTSW |
5 |
67,904,661 (GRCm39) |
missense |
possibly damaging |
0.82 |
|
R1897:Atp8a1
|
UTSW |
5 |
67,895,772 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1968:Atp8a1
|
UTSW |
5 |
67,825,000 (GRCm39) |
missense |
probably benign |
0.05 |
|
R2965:Atp8a1
|
UTSW |
5 |
67,805,049 (GRCm39) |
missense |
probably benign |
0.28 |
|
R2966:Atp8a1
|
UTSW |
5 |
67,805,049 (GRCm39) |
missense |
probably benign |
0.28 |
|
R4247:Atp8a1
|
UTSW |
5 |
67,824,917 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4353:Atp8a1
|
UTSW |
5 |
67,926,451 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4400:Atp8a1
|
UTSW |
5 |
67,922,221 (GRCm39) |
missense |
probably benign |
0.13 |
|
R4426:Atp8a1
|
UTSW |
5 |
67,932,171 (GRCm39) |
missense |
probably benign |
0.22 |
|
R4523:Atp8a1
|
UTSW |
5 |
67,824,943 (GRCm39) |
missense |
probably benign |
0.00 |
|
R4576:Atp8a1
|
UTSW |
5 |
67,973,158 (GRCm39) |
intron |
probably benign |
|
|
R4622:Atp8a1
|
UTSW |
5 |
67,840,056 (GRCm39) |
intron |
probably benign |
|
|
R4639:Atp8a1
|
UTSW |
5 |
67,813,317 (GRCm39) |
missense |
probably benign |
0.36 |
|
R4664:Atp8a1
|
UTSW |
5 |
67,919,929 (GRCm39) |
missense |
possibly damaging |
0.92 |
|
R4732:Atp8a1
|
UTSW |
5 |
67,970,463 (GRCm39) |
missense |
probably benign |
0.07 |
|
R4733:Atp8a1
|
UTSW |
5 |
67,970,463 (GRCm39) |
missense |
probably benign |
0.07 |
|
R5071:Atp8a1
|
UTSW |
5 |
67,973,066 (GRCm39) |
missense |
probably benign |
0.29 |
|
R5267:Atp8a1
|
UTSW |
5 |
67,919,887 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5314:Atp8a1
|
UTSW |
5 |
67,863,248 (GRCm39) |
critical splice donor site |
probably null |
|
|
R5424:Atp8a1
|
UTSW |
5 |
67,969,443 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5588:Atp8a1
|
UTSW |
5 |
67,972,027 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R5698:Atp8a1
|
UTSW |
5 |
67,924,496 (GRCm39) |
missense |
probably benign |
0.14 |
|
R5815:Atp8a1
|
UTSW |
5 |
67,906,414 (GRCm39) |
missense |
probably benign |
0.00 |
|
R5977:Atp8a1
|
UTSW |
5 |
67,904,628 (GRCm39) |
missense |
possibly damaging |
0.94 |
|
R6285:Atp8a1
|
UTSW |
5 |
67,824,950 (GRCm39) |
missense |
possibly damaging |
0.68 |
|
R6341:Atp8a1
|
UTSW |
5 |
67,840,270 (GRCm39) |
missense |
possibly damaging |
0.88 |
|
R6736:Atp8a1
|
UTSW |
5 |
67,824,960 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6746:Atp8a1
|
UTSW |
5 |
67,908,392 (GRCm39) |
missense |
probably benign |
0.00 |
|
R6887:Atp8a1
|
UTSW |
5 |
67,895,794 (GRCm39) |
missense |
probably benign |
0.21 |
|
R6946:Atp8a1
|
UTSW |
5 |
67,779,968 (GRCm39) |
missense |
possibly damaging |
0.50 |
|
R6970:Atp8a1
|
UTSW |
5 |
67,895,805 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7035:Atp8a1
|
UTSW |
5 |
67,938,373 (GRCm39) |
missense |
probably benign |
0.00 |
|
R7218:Atp8a1
|
UTSW |
5 |
67,860,324 (GRCm39) |
missense |
|
|
|
R7278:Atp8a1
|
UTSW |
5 |
67,781,380 (GRCm39) |
missense |
|
|
|
R7530:Atp8a1
|
UTSW |
5 |
67,902,971 (GRCm39) |
missense |
|
|
|
R7548:Atp8a1
|
UTSW |
5 |
67,973,071 (GRCm39) |
nonsense |
probably null |
|
|
R7594:Atp8a1
|
UTSW |
5 |
67,808,935 (GRCm39) |
missense |
|
|
|
R7722:Atp8a1
|
UTSW |
5 |
67,780,041 (GRCm39) |
critical splice acceptor site |
probably null |
|
|
R8152:Atp8a1
|
UTSW |
5 |
67,919,925 (GRCm39) |
missense |
|
|
|
R9015:Atp8a1
|
UTSW |
5 |
67,887,250 (GRCm39) |
missense |
|
|
|
R9052:Atp8a1
|
UTSW |
5 |
67,936,301 (GRCm39) |
critical splice donor site |
probably null |
|
|
R9086:Atp8a1
|
UTSW |
5 |
67,932,159 (GRCm39) |
missense |
|
|
|
R9169:Atp8a1
|
UTSW |
5 |
67,824,944 (GRCm39) |
missense |
|
|
|
R9183:Atp8a1
|
UTSW |
5 |
67,924,378 (GRCm39) |
missense |
|
|
|
R9245:Atp8a1
|
UTSW |
5 |
67,779,977 (GRCm39) |
missense |
unknown |
|
|
R9401:Atp8a1
|
UTSW |
5 |
67,906,492 (GRCm39) |
missense |
|
|
|
R9607:Atp8a1
|
UTSW |
5 |
67,817,250 (GRCm39) |
missense |
|
|
|
R9664:Atp8a1
|
UTSW |
5 |
67,889,524 (GRCm39) |
missense |
|
|
|
X0019:Atp8a1
|
UTSW |
5 |
67,906,484 (GRCm39) |
missense |
probably benign |
0.22 |
|
| Predicted Primers |
PCR Primer
(F):5'- AGCGCTATGTCCTTGAAATTCATC -3'
(R):5'- TGCTGCTGAACTTGTGTCTC -3'
Sequencing Primer
(F):5'- GAGATGAGCTCAGATCCACTTTTTC -3'
(R):5'- GTGTCTCTTCCAGATGTTAAACG -3'
|
| Posted On |
2019-06-07 |
Incidental Mutation