Task 7: Research SNPs

Lab journal Task 7

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HGMD (The Human Gene Mutation Database)

The search results for the HFE gene contain the different types of mutations that are specified in <xr id="hgmd"/>:

<figtable id="hgmd">

Table 1: Table of the different mutation types that were found for HFE in the HGMD.

mutation type	definition	number
missense, nonsense	mutation that leads to a change of amino acid or a stop codon	28
splicing	mutation that affects mRNA splicing	3
regulatory	substitiution causing abnormal regulation	1
small deletion	micro deletion (<= 20 bp)	4
small insertion	micro insertions (<= 20 bp)	1
small indel	micro indels (<= 20 bp)	0
gross deletion	delition > 20 bp	2
gross insertions/duplications	insertion > 20bp	0
complex rearrangments	rearrangements of stretches of the DNA sequence	1
repeat variations	differences in repeat length	0

</figtable>

In total, we found 40 mutation in the public version of the database and 49 in the non-public version.

<figtable id="hgmd missense">

Table 2: 28 missense and nonsense mutations for HFE from the HGMD.

accession number	codon change	aa change	codon number
CM032270	AGGc-AGC	Arg-Ser	6
CM091838	TTG-TGG	Leu-Trp	46
CM994469	cGTG-ATG	Val-Met	53
CM994470	cGTG-ATG	Val-Met	59
HM971246	CATg-CAC	His-His	63
CM960827	tCAT-GAT	His-Asp	63
CM990718	gAGT-TGT	Ser-Cys	65
CM033969	tCGC-TGC	Arg-Cys	66
CM020721	cCGA-TGA	Arg-Term	71
CM990719	aGGG-CGG	Gly-Arg	93
CM990720	ATT-ACT	Ile-Thr	105
CM990721	CAAg-CAC	Gln-His	127
CM091839	aGAC-AAC	Asp-Asn	129
CM091840	TACg-TAG	Tyr-Term	138
CM004810	gGAG-CAG	Glu-Gln	168
CM004106	gGAG-TAG	Glu-Term	168
CM004107	TGG-TAG	Trp-Term	169
CM015326	GCC-GTC	Ala-Val	176
CM081301	CTG-CCG	Leu-Pro	183
CM034097	CGG-CAG	Arg-Gln	224
CM101181	cCAG-TAG	Gln-Term	233
CM024530	tGTA-TTA	Val-Leu	272
CM994771	aGAG-AAG	Glu-Lys	277
CM960828	TGC-TAC
CM004391	TGC-TCC	Cys-Ser	282
CM032271	CAG-CCG	Gln-Pro	283
HM030028	GTG-GCG	Val-Ala	295
CM990722	AGG-ATG	Arg-Met	330

</figtable>

The 28 missense and nonsense mutations for HFE are listed in <xr id="hgmd missense"/> together with the amino acid (aa) change and the codon number.

dbSNP

dbSNP was searched to silent (synonymous) mutations of the HFE gene. Silent mutations are mutations in the nucleotide sequence that do not lead to a change in the amino acid sequence of the protein.

<figtable id="dbSNP silent">

Table 4: Mutations in the HFE protein from SNPdbe.

cluster ID	Function	mRNA pos	codon pos	nucleotide change	protein position	aa change
rs149342416	missense	178	3	G -> C	6	Arg -> Ser
rs114758821	synonymous	181	3	G -> A	7	Pro -> Pro
rs368895240	synonymous	190	3	C -> T	10	Leu -> Leu
rs201657128	missense	200	1	C -> G	14	Leu -> Val
rs143662783	missense	210	2	C -> T	17	Thr -> Ile
rs148161858	missense	228	2	G -> A	23	Arg -> His
rs2242956	missense	264	2	T -> C	35	Met -> Thr
rs377254261	missense	270	2	C -> T	37	Ala -> Val
rs147297176	synonymous	334	3	C -> T	58	Phe -> Phe
rs147426902	synonymous	349	3	T -> C	63	His -> His
rs139523708	missense	360	2	G -> A	67	Arg -> His
rs62625342	synonymous	388	3	C -> T	76	Ser -> Ser
rs376650371	missense	451	3	G -> A	97	Met -> Ile
rs199988202	missense	477	2	T -> C	106	Met -> Thr
rs200706856	missense	545	1	G -> A	129	Asp -> Asn
rs201885016	missense	549	2	A -> G	130	Asn -> Ser
rs369790080	synonymous	556	3	C -> T	132	Thr -> Thr
rs372789940	missense	581	1	G -> A	141	Asp -> Asn
rs199879669	missense	629	1	G -> C	157	Ala -> Pro
rs145475682	missense	644	1	G -> T	162	Ala -> Ser
rs148480830	synonymous	646	3	C -> G	162	Ala -> Ala
rs144170531	missense	656	1	A -> G	166	Lys -> Glu
rs146519482	missense	662	1	G -> C	168	Glu -> Gln
rs199916850	missense	708	2	T -> C	183	Leu -> Pro
rs140957442	nonsense	734	1	C -> T	192	Gln -> [Te
rs4986950	missense	810	2	C -> T	217	Thr -> Ile
rs144797937	missense	830	1	C -> T	224	Arg -> Trp
rs62625346	missense	831	2	G -> A	224	Arg -> Gln
rs140515012	missense	893	1	C -> G	245	Pro -> Ala
rs150402693	missense	913	3	C -> A	251	Phe -> Leu
rs182920795	synonymous	919	3	T -> A	253	Pro -> Pro
rs202068193	missense	926	1	G -> A	256	Val -> Ile
rs143846467	missense	936	2	A -> G	259	Asn -> Ser
rs140080192	missense	989	1	G -> A	277	Glu -> Lys
rs369354634	synonymous	1003	3	G -> A	281	Thr -> Thr
rs201310322	synonymous	1036	3	C -> T	292	Pro -> Pro
rs143175221	missense	1044	2	T -> C	295	Val -> Ala
rs114038675	synonymous	1054	3	G -> A	298	Glu -> Glu
rs372856303	synonymous	1063	3	G -> A	301	Pro -> Pro
rs147519426	missense	1104	2	T -> G	315	Val -> Gly
rs148632352	synonymous	1105	3	T -> C	315	Val -> Val
rs371192232	synonymous	1111	3	C -> T	317	Val -> Val
rs141229562	missense	1112	1	G -> A	318	Val -> Ile
rs150716212	missense	1125	2	T -> C	322	Ile -> Thr
rs138993448	missense	1140	2	T -> C	327	Ile -> Thr
rs368122334	missense	1179	2	G -> C	340	Gly -> Ala
rs35201683	synonymous	1186	3	C -> T	342	Tyr -> Tyr
rs370285936	missense	1188	2	T -> A	343	Val -> Asp
rs146508927	missense	1200	2	G -> A	347	Arg -> His

</figtable>

A list of the 35 mutations and their experimental evidence can be found in <xr id="snpdbe"/>.

OMIM

OMIM (Online Mendelian Inheritance in Man) also contains information about HFE, but only a small amount of all known mutations can be found.

<figtable id="omim">

Table 5: Mutations from OMIM that are associated with the HFE protein .

dbSNP accession	Phenotype	Mutation
rs1799945	HEMOCHROMATOSIS	HIS63ASP
rs1800730	HEMOCHROMATOSIS	SER65CYS
rs28934889	HFE POLYMORPHISM	VAL53MET
rs111033557	HFE POLYMORPHISM	VAL59MET
rs28934595	HEMOCHROMATOSIS	GLN127HIS
rs111033558	HEMOCHROMATOSIS	ARG330MET
rs28934596	HEMOCHROMATOSIS	ILE105THR
rs28934597	HEMOCHROMATOSIS	GLY93ARG
rs111033563	HEMOCHROMATOSIS	GLN283PRO

</figtable>

A complete list of the mutations can be found in <xr id="omim"/>. Two of the mutations are poylmorphisms of the HFE protein and 8 of them cause the disease hemochromatosis.

Databases comparison

<figtable id="comparison">

Table 6: .

database	last update	version	what information	where from	# entries homo sapiens	# HFE mutations
HGMD	spring 2013	public 2013.1 (mainly 3 year old data)	Collection of published gene lesions in the human genome that cause inherited diseases.	Only from publications. Journals are searched manually and by computational means each week.	99869	28 missense/nonsense
dbSNP	26.06.2012	Build 137	Short nucleotide sequence variations in different organisms (common and rare)	Submissions from laboratories but also private research companies.	192,678,553	10 synonymous, 41 non-synonymous, 10 disease causing SNPs and 162 SNPs in the UTR
SNPdbe	05.03.2012	-	Annotations for single amino acid substitutions (SAASs), e.g. functional effect (experimental, predicted), associated disease, evol. conservation,...	Based on entries from SwissProt, dbSNP, 1000 Genomes, PMD	967879	10 disease associated, 25 other
OMIM	daily	-	Compendium of human genes, genetic phenotypes and diseases. 3,035 genes with phenotype-causing mutations known.	Information from publications and databases is reviewed and summed up in texts by scientists.	21,934	2 8 disease causing mutations, 2 other

</figtable>

References

Stenson et al (2009), The Human Gene Mutation Database (HGMD®): 2008 Update. Genome Med 1(1):13
http://www.ncbi.nlm.nih.gov/books/NBK3848/
ftp://ftp.ncbi.nih.gov/pub/factsheets/Factsheet_SNP.pdf
https://www.rostlab.org/services/snpdbe/