Lab Journal - Task 8 (PAH)

Mutation dataset

For the generation of the mutation dataset the following five SNPs from the HGMD database were used (25th June 2013): <figtable id="mutds_hgmd">

Missense mutations (SNPs) from HGMD
Accession Number	Codon change	Sequence position	Amino acid change	Codon number	Disease	Reference
CM000542	CAG⇒CTG	59	Gln(Q)-Leu(L)	20	Hyperphenylalaninaemia	Hennermann (2000) Hum Mutat 15, 254
CM045080	GGT⇒AGT	307	Gly(G)-Ser(S)	103	Phenylketonuria	Lee (2004) J Hum Genet 49, 617
CM910286	GCC⇒GTC	776	Ala(A)-Val(V)	259	Phenylketonuria	Labrune (1991) Am J Hum Genet 48, 1115
CM010981	AAG⇒ACG	1022	Lys(K)-Thr(T)	341	Phenylketonuria	Tyfield (1997) Am J Hum Genet 60, 388
CM090791	CCA⇒CAA	1247	Pro(P)-Gln(Q)	416	Hyperphenylalaninaemia	Dobrowolski (2009) J Inherit Metab Dis 32, 10

</figtable>

Furthermore, the following five mutations from dbSNP were added (25th June 2013): <figtable id="mutds_dbSNP">

Missense mutations (SNPs) from dbSNP
Reference SNP	Codon change	Sequence position	Amino acid change	Codon number	Disease
rs199475569	CAC⇒AAC	190	His(H)-Asn(N)	64	?
rs199475681	AGA⇒ATA	368	Arg(R)-Ile(I)	123	?
rs62508752	ACA⇒CCA	796	Thr(T)-Ala(A)	266	Phenylketonuria
rs199475695	TTT⇒TCT	1175	Phe(F)-Ser(S)	392	?
rs199475696	ATT⇒ACT	1262	Ile(I)-Thr(T)	421	?

</figtable>

SIFT

• A259V

Substitution at pos 20 from Q to L is predicted to be TOLERATED with a score of 0.16.
   Median sequence conservation: 3.20
   Sequences represented at this position:42

• R123I

Substitution at pos 64 from H to N is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.01
   Sequences represented at this position:77

• Q20L

Substitution at pos 103 from G to S is predicted to be TOLERATED with a score of 0.90.
   Median sequence conservation: 3.02
   Sequences represented at this position:72

• G103S

Substitution at pos 123 from R to I is predicted to be TOLERATED with a score of 0.05.
   Median sequence conservation: 3.01
   Sequences represented at this position:76

• H64N

Substitution at pos 259 from A to V is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.01
   Sequences represented at this position:77

• I421T

Substitution at pos 266 from T to A is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.01
   Sequences represented at this position:77

• K341T

Substitution at pos 341 from K to T is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.01
   Sequences represented at this position:77

• F392S

Substitution at pos 392 from F to S is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.01
   Sequences represented at this position:77

• P416Q

Substitution at pos 416 from P to Q is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.00
   Sequences represented at this position:74

• T266A

Substitution at pos 421 from I to T is predicted to AFFECT PROTEIN FUNCTION with a score of 0.00.
   Median sequence conservation: 3.00
   Sequences represented at this position:74

PolyPhen2

• A259V

HumDiv
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)
HumVar
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)

• R123I

HumDiv
This mutation is predicted to be possibly damaging with a score of 0.807 (sensitivity: 0.84; specificity: 0.93)
HumVar
This mutation is predicted to be possibly damaging with a score of 0.582 (sensitivity: 0.81; specificity: 0.83)

• Q20L

HumDiv
This mutation is predicted to be benign with a score of 0.000 (sensitivity: 1.00; specificity: 0.00)
HumVar
This mutation is predicted to be benign with a score of 0.000 (sensitivity: 1.00; specificity: 0.00)

• G103S

HumDiv
This mutation is predicted to be benign with a score of 0.003 (sensitivity: 0.98; specificity: 0.44)
HumVar
This mutation is predicted to be benign with a score of 0.006 (sensitivity: 0.97; specificity: 0.45)

• H64N

HumDiv
This mutation is predicted to be probably damaging with a score of 0.993 (sensitivity: 0.70; specificity: 0.97)
HumVar
This mutation is predicted to be probably damaging with a score of 0.962 (sensitivity: 0.62; specificity: 0.92)

• I421T

HumDiv
This mutation is predicted to be possibly damaging with a score of 0.667 (sensitivity: 0.86; specificity: 0.91)
HumVar
This mutation is predicted to be probably damaging with a score of 0.913 (sensitivity: 0.69; specificity: 0.90)

• K341T

HumDiv
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)
HumVar
This mutation is predicted to be probably damaging with a score of 0.996 (sensitivity: 0.36; specificity: 0.97)

• F392S

HumDiv
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)
HumVar
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)

• P416Q

HumDiv
This mutation is predicted to be probably damaging with a score of 0.996 (sensitivity: 0.55; specificity: 0.98)
HumVar
This mutation is predicted to be probably damaging with a score of 0.985 (sensitivity: 0.55; specificity: 0.94)

• T266A

HumDiv
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)
HumVar
This mutation is predicted to be probably damaging with a score of 1.000 (sensitivity: 0.00; specificity: 1.00)

SNAP

• A259V
• R123I
• Q20L
• G103S
• H64N
• I421T
• K341T
• F392S
• P416Q
• T266A

MutationTaster

Gene: ENSG00000171759
Transcript: ENST00000553106
For affected protein features only those are reported that are annotated as "lost" and not as "might get lost".

• A259V - C776T

Prediction: disease causing, Model: simple_aae, prob: ~1 (classification due to ClinVar)
Summary: 
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CM910286)
•	known disease mutation: rs118203921 (pathogenic)
•	protein features (might be) affected (HELIX: 251-259, lost)
splice sites: Acc marginally increased

• R123I - G368T

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	listed as SNP
•	protein features (might be) affected
•	splice site changes (Acc increased)

• Q20L - A59T

Prediction: disease causing, Model: simple_aae, prob: ~0.95
Summary
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CM000542)
•	protein features (might be) affected
•	splice site changes (Donor lost, acc marginally increased)

• G103S - G307A

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CM045080)
•	protein features (might be) affected (Domain ACT: lost)
•	splice site changes (Donor gained)

• H64N - C190A

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CD993066)
•	protein features (might be) affected (Domain ACT: lost)

• I421T - T1262C

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	listed as SNP
•	protein features (might be) affected (STRAND: 420-424, lost)

• K341T - A1022C

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CM010980)
•	known disease mutation at this position (HGMD CM010981)
•	protein features (might be) affected (STRAND: 339-342, lost)

• F392S - T1175C

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	listed as SNP
•	protein features (might be) affected (HELIX: 392-403, lost)
•	splice site changes (Donor increased)

• P416Q - C1247A

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	known disease mutation at this position (HGMD CM090791)
•	protein features (might be) affected (TURN: 416-419, lost)
•	splice site changes (Acc marginally increased, donor increased, donor gained)

• T266A - A796C

Prediction: disease causing, Model: simple_aae, prob: ~1
Summary
•	amino acid sequence changed
•	listed as SNP
•	protein features (might be) affected 
•	splice site changes (Acc increased, acc gained, donor increased)