IGDRPT (Indian Genetic Disease Risk Prediction Tool)

Disease Name: Oculocutaneous Albinism type 1 (OCA1)

1 .Inheritance

Autosomal Recessive

2. Gene Name

TYR

3. Protein Name

Tyrosinase

4. Chromosomal Location

11q14-q21

5. Protein Sequence

>sp|P14679|TYRO_HUMAN Tyrosinase OS=Homo sapiens OX=9606 GN=TYR PE=1 SV=3

MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILL

SNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCTERRLLVR

RNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLFVWMH

YYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENFTIPYWDWRD

AEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTPEGPLRRN

PGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIADASQS

SMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPIGH

NRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLG

AAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQPLLMEKEDYHSLYQSHL

6. Gene Sequence

>NM_000372.4 Homo sapiens tyrosinase (TYR), mRNA

ATCACTGTAGTAGTAGCTGGAAAGAGAAATCTGTGACTCCAATTAGCCAGTTCCTGCAGACCTTGTGAGG

ACTAGAGGAAGAATGCTCCTGGCTGTTTTGTACTGCCTGCTGTGGAGTTTCCAGACCTCCGCTGGCCATT

TCCCTAGAGCCTGTGTCTCCTCTAAGAACCTGATGGAGAAGGAATGCTGTCCACCGTGGAGCGGGGACAG

GAGTCCCTGTGGCCAGCTTTCAGGCAGAGGTTCCTGTCAGAATATCCTTCTGTCCAATGCACCACTTGGG

CCTCAATTTCCCTTCACAGGGGTGGATGACCGGGAGTCGTGGCCTTCCGTCTTTTATAATAGGACCTGCC

AGTGCTCTGGCAACTTCATGGGATTCAACTGTGGAAACTGCAAGTTTGGCTTTTGGGGACCAAACTGCAC

AGAGAGACGACTCTTGGTGAGAAGAAACATCTTCGATTTGAGTGCCCCAGAGAAGGACAAATTTTTTGCC

TACCTCACTTTAGCAAAGCATACCATCAGCTCAGACTATGTCATCCCCATAGGGACCTATGGCCAAATGA

AAAATGGATCAACACCCATGTTTAACGACATCAATATTTATGACCTCTTTGTCTGGATGCATTATTATGT

GTCAATGGATGCACTGCTTGGGGGATCTGAAATCTGGAGAGACATTGATTTTGCCCATGAAGCACCAGCT

TTTCTGCCTTGGCATAGACTCTTCTTGTTGCGGTGGGAACAAGAAATCCAGAAGCTGACAGGAGATGAAA

ACTTCACTATTCCATATTGGGACTGGCGGGATGCAGAAAAGTGTGACATTTGCACAGATGAGTACATGGG

AGGTCAGCACCCCACAAATCCTAACTTACTCAGCCCAGCATCATTCTTCTCCTCTTGGCAGATTGTCTGT

AGCCGATTGGAGGAGTACAACAGCCATCAGTCTTTATGCAATGGAACGCCCGAGGGACCTTTACGGCGTA

ATCCTGGAAACCATGACAAATCCAGAACCCCAAGGCTCCCCTCTTCAGCTGATGTAGAATTTTGCCTGAG

TTTGACCCAATATGAATCTGGTTCCATGGATAAAGCTGCCAATTTCAGCTTTAGAAATACACTGGAAGGA

TTTGCTAGTCCACTTACTGGGATAGCGGATGCCTCTCAAAGCAGCATGCACAATGCCTTGCACATCTATA

TGAATGGAACAATGTCCCAGGTACAGGGATCTGCCAACGATCCTATCTTCCTTCTTCACCATGCATTTGT

TGACAGTATTTTTGAGCAGTGGCTCCGAAGGCACCGTCCTCTTCAAGAAGTTTATCCAGAAGCCAATGCA

CCCATTGGACATAACCGGGAATCCTACATGGTTCCTTTTATACCACTGTACAGAAATGGTGATTTCTTTA

TTTCATCCAAAGATCTGGGCTATGACTATAGCTATCTACAAGATTCAGACCCAGACTCTTTTCAAGACTA

CATTAAGTCCTATTTGGAACAAGCGAGTCGGATCTGGTCATGGCTCCTTGGGGCGGCGATGGTAGGGGCC

GTCCTCACTGCCCTGCTGGCAGGGCTTGTGAGCTTGCTGTGTCGTCACAAGAGAAAGCAGCTTCCTGAAG

AAAAGCAGCCACTCCTCATGGAGAAAGAGGATTACCACAGCTTGTATCAGAGCCATTTATAAAAGGCTTA

GGCAATAGAGTAGGGCCAAAAAGCCTGACCTCACTCTAACTCAAAGTAATGTCCAGGTTCCCAGAGAATA

TCTGCTGGTATTTTTCTGTAAAGACCATTTGCAAAATTGTAACCTAATACAAAGTGTAGCCTTCTTCCAA

CTCAGGTAGAACACACCTGTCTTTGTCTTGCTGTTTTCACTCAGCCCTTTTAACATTTTCCCCTAAGCCC

ATATGTCTAAGGAAAGGATGCTATTTGGTAATGAGGAACTGTTATTTGTATGTGAATTAAAGTGCTCTTA

TTTTAAAAAATTGAAATAATTTTGATTTTTGCCTTCTGATTATTTAAAGATCTATATATGTTTTATTGGC

CCCTTCTTTATTTTAATAAAACAGTGAGAAATCTAAAAAAAAAAAAAAAAAA

7. Motif

Pfam (4 motifs)

Pfam	Position(Independent E-value)	Description
Tyrosinase	172..402(4.9e-43)	PF00264, Common central domain of tyrosinase
Laminin_EGF	87..110(0.0019)	PF00053, Laminin EGF domain
LapA_dom	472..507(0.074)	PF06305, Lipopolysaccharide assembly protein A domain
Nup188_SH3-like	147..159(0.28)	PF21094, Nup188 SH3-like domain

8. Evolutionary Relationship

Evolutionary analysis by Maximum Likelihood method

The evolutionary history was inferred by using the Maximum Likelihood method and JTT matrix-based model [1]. The tree with the highest log likelihood (-8876.70) is shown. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using a JTT model, and then selecting the topology with superior log likelihood value. The proportion of sites where at least 1 unambiguous base is present in at least 1 sequence for each descendent clade is shown next to each internal node in the tree. This analysis involved 100 amino acid sequences. There were a total of 679 positions in the final dataset.

9. SNP

SNP	COORDINATE	AMINO ACID CHANGE	GENE ID	TRANSCRIPT ID	PROTEIN ID	SIFT SCORE	SIFT MEDIAN	SIFT PREDICTION
rs1126809	89017961	R402Q	ENSG00000077498	ENST00000263321	ENSP00000263321	0.08	2.44	TOLERATED
rs28940876	88911363	P81L	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs28940877	88911386	C89R	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs28940878	88911246	D42G	ENSG00000077498	ENST00000263321	ENSP00000263321	0.211	2.55	TOLERATED
rs28940879	88911285	C55Y	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs28940879	88911285	C55S	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs28940880	88911737	A206T	ENSG00000077498	ENST00000263321	ENSP00000263321	0.004	2.44	DELETERIOUS
rs28940881	88911122	M1V	ENSG00000077498	ENST00000263321	ENSP00000263321	0.343	2.79	TOLERATED
rs61753178	88911182	P21S	ENSG00000077498	ENST00000263321	ENSP00000263321	0.009	2.55	DELETERIOUS
rs61753180	88911261	G47D	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.55	DELETERIOUS
rs61753184	88911350	R77W	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs61753185	88911351	R77Q	ENSG00000077498	ENST00000263321	ENSP00000263321	0.001	2.54	DELETERIOUS
rs61753256	88911467	R116*	ENSG00000077498	ENST00000263321	ENSP00000263321
rs61754360	88911654	W178*	ENSG00000077498	ENST00000263321	ENSP00000263321
rs61754362	88911734	P205T	ENSG00000077498	ENST00000263321	ENSP00000263321	0.002	2.44	DELETERIOUS
rs61754363	88911767	L216M	ENSG00000077498	ENST00000263321	ENSP00000263321	0.02	2.44	DELETERIOUS
rs61754365	88911771	R217Q	ENSG00000077498	ENST00000263321	ENSP00000263321	0.371	2.44	TOLERATED
rs61754367	88911828	W236*	ENSG00000077498	ENST00000263321	ENSP00000263321
rs61754367	88911828	W236S	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.43	DELETERIOUS
rs61754374	88924445	R299S	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.46	DELETERIOUS
rs61754375	88924446	R299H	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.46	DELETERIOUS
rs61754380	88924532	E328Q	ENSG00000077498	ENST00000263321	ENSP00000263321	0.002	2.44	DELETERIOUS
rs61754386	88961065	N371Y	ENSG00000077498	ENST00000263321	ENSP00000263321	0.002	2.44	DELETERIOUS
rs61754387	88961066	N371T	ENSG00000077498	ENST00000263321	ENSP00000263321	0.004	2.44	DELETERIOUS
rs61754388	88961072	T373K	ENSG00000077498	ENST00000263321	ENSP00000263321	0.003	2.44	DELETERIOUS
rs61754392	89018011	G419R	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.48	DELETERIOUS
rs61754393	89018021	R422Q	ENSG00000077498	ENST00000263321	ENSP00000263321	0.202	2.48	TOLERATED
rs62645904	88924382	R278*	ENSG00000077498	ENST00000263321	ENSP00000263321
rs62645916	89017955	W400L	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.44	DELETERIOUS
rs62645917	89017960	R402*	ENSG00000077498	ENST00000263321	ENSP00000263321
rs63159160	88911770	R217G	ENSG00000077498	ENST00000263321	ENSP00000263321	0.376	2.44	TOLERATED
rs63159160	88911770	R217W	ENSG00000077498	ENST00000263321	ENSP00000263321	0.187	2.44	TOLERATED
rs104894313	89017973	P406L	ENSG00000077498	ENST00000263321	ENSP00000263321	0.004	2.47	DELETERIOUS
rs104894314	88924373	V275F	ENSG00000077498	ENST00000263321	ENSP00000263321	0.004	2.44	DELETERIOUS
rs104894315	88961100	N382K	ENSG00000077498	ENST00000263321	ENSP00000263321	0.001	2.44	DELETERIOUS
rs104894315	88961100	N382N	ENSG00000077498	ENST00000263321	ENSP00000263321	1	2.44	TOLERATED
rs104894316	89017965	R403S	ENSG00000077498	ENST00000263321	ENSP00000263321	0.008	2.44	DELETERIOUS
rs104894317	89018092	G446S	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.51	DELETERIOUS
rs104894318	89018098	D448N	ENSG00000077498	ENST00000263321	ENSP00000263321	0.091	2.51	TOLERATED
rs104894318	89018098	D448H	ENSG00000077498	ENST00000263321	ENSP00000263321	0.023	2.51	DELETERIOUS
rs121908011	88961101	D383N	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.44	DELETERIOUS
rs137854890	88911393	C91Y	ENSG00000077498	ENST00000263321	ENSP00000263321	0	2.54	DELETERIOUS
rs151206295	88961018	A355V	ENSG00000077498	ENST00000263321	ENSP00000263321	0.461	2.49	TOLERATED

Evolutionary analysis of coding SNPs

SNP	Substitution	Probability of deleterious effect	Prediction Score
rs1126809	R402Q	probably damaging	0.74
rs28940876	P81L	probably damaging	0.85
rs28940877	C89R	probably damaging	0.85
rs28940878	D42G	probably damaging	0.74
rs28940879	C55Y	probably damaging	0.85
rs28940879	C55S	probably damaging	0.85
rs28940880	A206T	probably benign	0.19
rs28940881	M1V	probably damaging	0.74
rs61753178	P21S	probably damaging	0.85
rs61753180	G47D	probably damaging	0.85
rs61753184	R77W	probably damaging	0.85
rs61753185	R77Q	probably damaging	0.85
rs61753256	P205T	probably damaging	0.85
rs61754360	L216M	probably damaging	0.85
rs61754362	R217Q	probably benign	0.19
rs61754363	W236S	probably damaging	0.89
rs61754365	R299S	probably damaging	0.85
rs61754367	R299H	probably damaging	0.85
rs61754367	E328Q	possibly damaging	0.5
rs61754374	N371Y	probably damaging	0.74
rs61754375	N371T	probably damaging	0.74
rs61754380	T373K	probably benign	0.27
rs61754386	G419R	probably damaging	0.85
rs61754387	R422Q	probably damaging	0.57
rs61754388	W400L	probably damaging	0.89
rs61754392	R217G	probably benign	0.19
rs61754393	R217W	probably benign	0.19
rs62645904	P406L	possibly damaging	0.5
rs62645916	V275F	probably benign	0.13
rs62645917	N382K	probably damaging	0.85
rs63159160	N382N	probably damaging	0.85
rs63159160	R403S	probably damaging	0.85
rs104894313	G446S	probably damaging	0.85
rs104894314	D448N	possibly damaging	0.5
rs104894315	D448H	possibly damaging	0.5
rs104894315	D383N	probably damaging	0.85
rs104894316	C91Y	probably damaging	0.85
rs104894317	A355V	possibly damaging	0.5

Provean

SNP Id’s	Amino Acid Change	probability	Prediction	Score
rs1126809	R402Q	Neutral	Damaging	-1.82
rs28940876	P81L	Deleterious	Damaging	-9.31
rs28940877	C89R	Deleterious	Damaging	-11.39
rs28940878	D42G	Deleterious	Tolerated	-2.69
rs28940879	C55Y	Deleterious	Damaging	-9.68
rs28940879	C55S	Deleterious	Damaging	-8.79
rs28940880	A206T	Deleterious	Damaging	-3.26
rs28940881	M1V	Neutral	Damaging	-0.78
rs61753178	P21S	Deleterious	Damaging	-6.27
rs61753180	G47D	Deleterious	Damaging	-6.06
rs61753184	R77W	Deleterious	Damaging	-7.5
rs61753185	R77Q	Deleterious	Damaging	-3.74
rs61754362	P205T	Deleterious	Damaging	-6.95
rs61754363	L216M	Neutral	Damaging	-1.82
rs61754365	R217Q	Neutral	Tolerated	0.25
rs61754367	W236S	Deleterious	Damaging	-11.95
rs61754374	R299S	Deleterious	Damaging	-4.56
rs61754375	R299H	Deleterious	Damaging	-3.78
rs61754380	E328Q	Neutral	Damaging	-1.66
rs61754386	N371Y	Deleterious	Damaging	-5.96
rs61754387	N371T	Deleterious	Damaging	-4.47
rs61754388	T373K	Deleterious	Damaging	-3.79
rs61754392	G419R	Deleterious	Damaging	-5.7
rs61754393	R422Q	Neutral	Damaging	-1.66
rs62645916	W400L	Deleterious	Damaging	-9.64
rs63159160	R217G	Neutral	Tolerated	-1.64
rs63159160	R217W	Neutral	Tolerated	-0.66
rs104894313	P406L	Deleterious	Damaging	-4.3
rs104894314	V275F	Deleterious	Damaging	-2.79
rs104894315	N382K	Deleterious	Damaging	-4.41
rs104894315	N382N	Neutral	Tolerated	0
rs104894316	R403S	Deleterious	Damaging	-3.53
rs104894317	G446S	Deleterious	Damaging	-4.37
rs104894318	D448N	Neutral	Tolerated	-0.35
rs104894318	D448H	Neutral	Damaging	-1.15
rs121908011	D383N	Deleterious	Damaging	-3.71
rs137854890	C91Y	Deleterious	Damaging	-10.44
rs151206295	A355V	Neutral	Tolerated	-0.49

SNAP2

Wildtype amino acid	Position	Variant Amnio Acid	Predicted Effect	Score	Expected Accuracy
R	402	Q	Effect	89	95%
P	81	L	Effect	56	95%
C	89	R	Effect	76	87%
D	42	G	Effect	34	80%
C	55	Y	Effect	67	65%
C	55	S	Effect	87	75%
A	206	R	Effect	45	90%
M	1	G	Neutral	34	95%
P	21	Y	Effect	76	45%
G	47	S	Effect	56	35%
R	77	T	Effect	45	70%
R	77	V	Effect	98	70%
P	205	S	Effect	23	87%
G	216	D	Neutral	-25	80%
R	217	W	Neutral	78	65%
R	236	Q	Neutral	65	75%
P	78	T	Effect	45	90%
L	216	M	Effect	67	95%
R	217	Q	Effect	87	45%
W	236	S	Effect	90	35%
R	299	S	Effect	56	89%

Polyphen 2

Rs_Id	Mutation Probability	Score
rs1126809	Probably damaging	0.999
rs28940876	Probably damaging	0.999
rs28940877	Possibly damaging	1.00
rs28940878	Probably damaging	0.999
rs28940879	Probably damaging	0.98
rs28940879	Possibly damaging	0.98
rs28940880	Possibly damaging	1.00
rs28940881	Probably damaging	0.999
rs61753178	Possibly damaging	1.00
rs61753180	Probably damaging	0.98
rs61753184	Possibly damaging	1.00
rs61753185	Probably damaging	0.999
rs61754362	Possibly damaging	1.00
rs61754363	Probably damaging	1.00
rs61754365	Probably damaging	0.98
rs61754367	Probably damaging	0.98
rs61754374	Possibly damaging	1.00
rs61754375	Probably damaging	0.999
rs61754380	Probably damaging	0.999
rs61754386	Probably damaging	0.98
rs61754387	Possibly damaging	1.00
rs61754388	Probably damaging	0.999
rs61754392	Possibly damaging	1.00
rs61754393	Probably damaging	1.00
rs62645916	Probably damaging	0.98
rs63159160	Possibly damaging	1.00
rs63159160	Probably damaging	0.999
rs104894313	Probably damaging	0.999
rs104894314	Possibly damaging	1.00
rs104894315	Probably damaging	0.999
rs104894315	Probably damaging	0.999
rs104894316	Possibly damaging	1.00
rs104894317	Probably damaging	0.999
rs104894318	Possibly damaging	1.00
rs104894318	Probably damaging	1.00
rs121908011	Probably damaging	0.999
rs137854890	Probably damaging	0.999
rs151206295	Probably damaging	0.999

10. Active Site

Nil

11. Primary Sequence Analysis

Number of amino acids

529

Molecular weight

60393.27

Theoretical pI

5.71

Amino acid composition

Ala (A) 30 5.7%

Arg (R) 27 5.1%

Asn (N) 27 5.1%

Asp (D) 30 5.7%

Cys (C) 17 3.2%

Gln (Q) 23 4.3%

Glu (E) 27 5.1%

Gly (G) 34 6.4%

His (H) 17 3.2%

Ile (I) 22 4.2%

Leu (L) 55 10.4%

Lys (K) 17 3.2%

Met (M) 15 2.8%

Phe (F) 31 5.9%

Pro (P) 33 6.2%

Ser (S) 51 9.6%

Thr (T) 19 3.6%

Trp (W) 14 2.6%

Tyr (Y) 23 4.3%

Val (V) 17 3.2%

Pyl (O) 0 0.0%

Sec (U) 0 0.0%

Total number of negatively charged residues (Asp + Glu)

Total number of positively charged residues (Arg + Lys)

Formula

C₂₇₀₉H₄₀₅₁N₇₂₅O₇₈₇S₃₂

Total number of atoms

8304

Instability index(II)

56.76

Stability

unstable

Aliphatic index(AI)

71.76

GRAVY

-0.356

12. Secondary structure analysis

Alpha helix (Hh) : 118 is 22.31%

310 helix (Gg) : 0 is 0.00%

Pi helix (Ii) : 0 is 0.00%

Beta bridge (Bb) : 0 is 0.00%

Extended strand (Ee) : 45 is 8.51%

Beta turn (Tt) : 0 is 0.00%

Bend region (Ss) : 0 is 0.00%

Random coil (Cc) : 366 is 69.19%

Ambiguous states (?) : 0 is 0.00%

Other states : 0 is 0.00%

Secondary Structure Prediction

Amino Acid Type

13. Enzymes

Name of enzyme	No of cleavages
Arg-C protEinase	27
Asn-N endonentidase	30
Asn-N endonentidase+ N-terminal Glu	57
BNPS-Skatole	14
CBr	15
Cbymotrynsin-bi9h snecificity (C-term to fFYWl, not before P)	63
Cbymotrynsin-low snecificity (C-term to rFYWMLl, not beoreP)	145
Clostripain	27
Formic acid	30
Glutamylendooentidase	27
Iodosobenzoic acid	14
Hydroxylamine	4
LysC	17
LysN	17
NTCB (2-nitro-5-tbiocyanobenzoicacid)	17
Pepsin (pHl.3)	111
Pepsin (pH>2)	159
Proline-mdopeptidase	2
Proteinase K	238
Staphylococcal peptidase I	25
Thermolysin	139
Thrombin	1
Trypsin	42

14. Epitope

Rank	Start Position	Sequence	Score	Prediction
1	150	VIPIGTYGQMKNGSTP	0.98	Epitope
2	230	NFTIPYWDWRDAEKCD	0.96	Epitope
3	290	NGTPEGPLRRNPGNHD	0.95	Epitope
4	365	ALHIYMNGTMSQVQGS	0.92	Epitope
4	323	SLTQYESGSMDKAANF	0.92	Epitope
5	52	RGSCQNILLSNAPLGP	0.91	Epitope
5	307	SRTPRLPSSADVEFCL	0.91	Epitope
6	75	DDRESWPSVFYNRTCQ	0.90	Epitope
7	191	GSEIWRDIDFAHEAPA	0.89	Epitope
7	157	GQMKNGSTPMFNDINI	0.89	Epitope

15. Protein-Protein Interaction

No of Nodes	11
No of Edges	30
Avg node degree	5.45
avg. local clustering coefficient	0.925
expected number of e, dges	10
p-value	4.68e-07
Protein – Protein Interaction network

16. MRNA

RNA Base Pairing Probability Plot