ADA K80R - GET-Evidence

Curation:
Currentness:

ADA K80R

(ADA Lys80Arg)


Short summary

This variant has a 3.5% allele frequency in 1000 genomes data. Although OMIM links this to disease, the paper they reference uses in vitro data to conclude that this is a functionally neutral polymorphism.

Variant evidence
Computational 1

Amino acid change not disruptive.

Functional 1

Homozygous cell line has normal activity.

See Valerio D et al. 1984 (6198631).

Case/Control 5

Frequency of allele strongly contradicts this variant as causing ADA-deficiency or SCID.

See unpublished research (below).

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

recessive

Summary of published research, and additional commentary

The prevalence of severe diseases caused by recessive defects in ADA — severe combined immunodeficiency and ADA deficiency — is extremely rare (1 / 100,000 is a high end estimate). This variant was seen in 9 out of 128 random PGP + public alleles, contradict such an effect.

To demonstrate significance, we compare observations against the allele frequency that would be expected for a pathogenic variant causing ADA deficiency. A variant responsible for 20% of disease would be expected to have an allele frequency of .06% (.2 * (1 / 100,000)**0.5). The chances of seeing such a variant 9 times in 128 random alleles is extremely low (4 * 10^-16).

Allele frequency

  • C @ chr20:43255220: 6.4% (684/10758) in EVS
  • C @ chr20:42688633: 7.0% (9/128) in GET-Evidence
  • Frequency shown in summary reports: 6.4% (684/10758)

Publications
 

Valerio D, Duyvesteyn MG, van Ormondt H, Meera Khan P, van der Eb AJ. Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein. Nucleic Acids Res. 1984 Jan 25;12(2):1015-24. PubMed PMID: 6198631; PubMed Central PMCID: PMC318552.

A patient (GM2471) with severe combined immunodeficiency caused by inherited ADA deficiency was found to be heterozygous for both K80R and L304R. A cell line homozygous for the K80R variant was shown to have normal ADA activity and so the authors conclude that this is a functionally neutral polymorphism and not responsible for the patient’s phenotype. The L304R was implicated instead, observed to inactivate ADA.

Sanchez JJ, Monaghan G, Børsting C, Norbury G, Morling N, Gaspar HB. Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry. Ann Hum Genet. 2007 May;71(Pt 3):336-47. Epub 2007 Dec 19. PubMed PMID: 17181544.

 

Genomes
 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr20:43255220

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het C @ chr20:43255220

 

 

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het C @ chr20:43255220

 

GS06994 - var-GS06994-1100-36-ASM
het C @ chr20:42688634

 

GS12004 - var-GS12004-1100-36-ASM
het C @ chr20:42688634

 

GS19017 - var-GS19017-1100-36-ASM
hom C @ chr20:42688634

 

GS19020 - var-GS19020-1100-36-ASM
het C @ chr20:42688634

 

GS19026 - var-GS19026-1100-36-ASM
het C @ chr20:42688634

 

GS20502 - var-GS20502-1100-36-ASM
het C @ chr20:42688634

 

Other external references
 

    dbSNP
  • rs11555566
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (15 hits -- see all)
  • Carrier frequency of a nonsense mutation in the adenosine ...
    Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that ... (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA ...
    www.ncbi.nlm.nih.gov/pubmed/17181544
  • ADAbase: Adenosine deaminase deficiency (ADA) | Public Database |
    Mutation registry for Adenosine deaminase deficiency (ADA) ... leading to Comment amino acid substitution K80R, which is known Comment as a ...
    bioinf.uta.fi/ADAbase/index.php?content=pub/IDbases
  • AceView: Gene:ADA, 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=ADA
  • Epidemiology of Human Influenza A and B Viruses in Myanmar ...
    K80R. K48E. V87S. N75S. I389S. L52S. K419N. S397I. E404K. E320D. N220K. V271I. T42S. S41P. Fig. 4. ... Deng YM, Iannello P, et al: Ada- mantane resistance in influenza A(H1) ...
    content.karger.com/ProdukteDB/produkte.asp?...
  • katarogu
    ... FlateDecode ] /Length 5 0 R >> stream 8;Rb?ku6(,*IpB3hu1_a&oo'Za?^<=O? ... [moL:si4[mim^ o`=AU[^FN#do3;d]TItA@0@d/AkJ^Z5`^`q?pB!,R%sWbS)8nlHN&-Pk^cg[@CDgd ...
    www.sweet144model.com/tobipage/katarogu
  • Mai 2008
    Tundrakaur Gav ada 1r. 27.05.2008. Per K Linderum. Matsu, Ridala v. Aed-roolind Acr dum 1s ... Mustlagle Bra ber k80r N. Merikotkas Hal alb k2''p. Väike-kärbsenäpp ...
    www.llk.ee/obs/news0805.htm
  • IngentaConnect Carrier Frequency of a Nonsense Mutation in ...
    Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that ... (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA ...
    ingentaconnect.com/content/.../00000071/00000003/art00007
  • Carrier Frequency of a Nonsense Mutation in the Adenosine ...
    Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that ... (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA ...
    www3.interscience.wiley.com/journal/120118253/abstract
  • OMIM: 608958
    ADA immunoreactive protein and translatable ADA mRNA were found to be ... ADA gene: a T-to-G transversion in exon 10, resulting in a leu304-to-arg (L304R) substitution and K80R ...
    www.genome.jp/dbget-bin/www_bget?mim:608958

Other in silico analyses
 

  • NBLOSUM100 score = –3
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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