TYR S192Y - GET-Evidence

Curation:
Currentness:

TYR S192Y

(TYR Ser192Tyr)


Short summary

This variant is reported to affect skin pigmentation. It is associated with lighter skin in South Asians (OR 4-5) and with a lack of freckles in Europeans (OR 1.3).

Variant evidence
Computational 2

Other variants in this gene associated with pigmentation, amino acid change predicted to be disruptive (BLOSUM100 = 3), polyphen predicts “possibly damaging”

Functional -
Case/Control 5

OR of 4-5 range for dark vs. light skin in South Asians, extremely low p value

See Stokowski RP et al. 2007 (17999355).

Familial
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Likely benign

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr11:88911696: 27.1% (2912/10758) in EVS
  • A @ chr11:88551343: 21.9% (28/128) in GET-Evidence
  • Frequency shown in summary reports: 27.1% (2912/10758)

Publications
 

Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Pálsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet. 2007 Dec;39(12):1443-52. Epub 2007 Oct 21. PubMed PMID: 17952075.

This variant was associated with a lack of freckles in Europeans (OR 1.3) but had not significant associations with eye color, hair color, or sun sensitivity. The variant (the “A” allele) appears to have undergone strong positive selection in Europeans.

Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR. A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet. 2007 Dec;81(6):1119-32. Epub 2007 Oct 15. PubMed PMID: 17999355; PubMed Central PMCID: PMC2276347.

A study of South Asians found this variant significantly associated with lighter skin. Participants were split into quintiles based on skin reflectence and the highest vs. lowest compared, this variant had an odds ratio of 4-5 for the lighter skin group, 6.5 * 10^-11

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het A @ chr11:88911696

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom A @ chr11:88911696

 

hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het A @ chr11:88911696

 

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr11:88911696

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
hom A @ chr11:88911696

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het A @ chr11:88911696

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het A @ chr11:88911696

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
hom A @ chr11:88911696

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr11:88911696

 

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het A @ chr11:88911696

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het A @ chr11:88911696

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr11:88911696

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr11:88911696

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het A @ chr11:88911696

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
hom A @ chr11:88911696

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom A @ chr11:88911696

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het A @ chr11:88911696

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het A @ chr11:88911696

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr11:88911696

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
hom A @ chr11:88911696

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr11:88911696

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr11:88551344

 

GS06994 - var-GS06994-1100-36-ASM
hom A @ chr11:88551344

 

GS07357 - var-GS07357-1100-36-ASM
het A @ chr11:88551344

 

GS19670 - var-GS19670-1100-36-ASM
het A @ chr11:88551344

 

GS20502 - var-GS20502-1100-36-ASM
hom A @ chr11:88551344

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr11:88551344

 

NA12878

 

Other external references
 

    dbSNP
  • rs1042602
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Freckles (rs1042602-C)
    Sulem 21-Oct-07 in Nat Genet
    OR or beta: 1.32 [1.17-1.49]
    Risk allele frequency: 0.67
    p-value: 2.00E-11
    Initial sample: 2,986 individuals
    Replication sample: 3,932 individuals
    www.ncbi.nlm.nih.gov/pubmed/17952075
  • Skin pigmentation (rs1042602-C)
    Stokowski 15-Oct-07 in Am J Hum Genet
    OR or beta: 4.36 [2.64-7.20]
    Risk allele frequency: 0.84
    p-value: 4.00E-10
    Initial sample: 363 with maxL* < 56 and 374 with maxL* > 63; 20% tails of distribution
    Replication sample: 116 low maxL*, 115 high maxL* individuals
    www.ncbi.nlm.nih.gov/pubmed/17999355
    PolyPhen-2
  • Score: 0.919 (probably damaging)
    Web search results (29 hits -- see all)
  • Of Mice and Men: Tyrosinase Modification of Congenital ...
    Recently, tyrosinase (Tyr) deficiency was found to worsen the drainage structure ... the TYR chromosomal region 11q13-q21, and sequencing of the TYR gene ...
    www.iovs.org/cgi/content/full/47/4/1486
  • Of Mice and Men: Tyrosinase Modification of Congenital ...
    tyrosinase (Tyr) deficiency was found to worsen the drainage ... in the TYR chromosomal region 11q13- q21, and sequencing of the TYR gene was performed ...
    www.iovs.org/cgi/reprint/47/4/1486.pdf
  • Chaki, Mol Vis 2005; 11:531-534.
    A lack of tyrosinase (TYR) activity among all the patients was ascertained by ... Haplotype analysis was performed at the TYR locus using a set of informative ...
    www.molvis.org/molvis/v11/a62
  • AceView: Gene:TYR, a comprehensive annotation of human, mouse ...
    AceView offers a comprehensive annotation of human, mouse and nematode genes reconstructed by co-alignment and clustering of all publicly available mRNAs and ESTs on ...
    ncbi.nlm.nih.gov/IEB/Research/Acembly/...&a=clones&l=TYR
  • Higher prevalence of OCA1 in an ethnic group of eastern India ...
    A lack of tyrosinase (TYR) activity among all the patients was ascertained by ... screening in the tyrosinase gene (TYR) was done by single strand conformational ...
    www.molvis.org/molvis/v11/a62/v11a62-chaki.pdf
  • A Genomewide Association Study of Skin Pigmentation in a ...
    These included the nonsynonymous polymorphisms in TYR and SLC45A2, as well as 30 ... and rs1042602 (p.S192Y) in TYR—that show genomewide significance ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2276347/?tool=EBI
  • Potential etiologic and functional implications of genome ...
    Genome Technology Branch, National Human Genome Research Institute, and ... S192Y. rs1042602. TYR. TYR. Freckles. CDP only. rs6046. R413Q. rs561241. Factor VII. Factor VII ...
    genome.gov/Pages/.../News&Features/PNASGWASOnlineCatalog.pdf
  • OMIM: 606933
    MC1R and TYR are associated with pigmentation, freckling, and cutaneous sun ... found association of the TYR SNP dbSNP rs1042602 (S192Y) with skin pigmentation. ...
    www.genome.jp/dbget-bin/www_bget?omim+606933

Other in silico analyses
 

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

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