SIAE M89V - GET-Evidence



(SIAE Met89Val)

Short summary

This variant was reported to be associated with autoimmune disease when homozygous. However, a later publication has contradicted this result, finding no significant association between this variant and autoimmune disease in a very large cohort.

Variant evidence
Computational 2

Polyphen predicts “possibly damaging”. Surolia et al. find other variants in this gene associated with autoimmune disease.

See Surolia I et al. 2010 (20555325).

Functional 2

Protein product with this variant is catalytically active but is not secreted. This finding was reproduced in a pulse-chase experiment with 35S-methionine.

See Surolia I et al. 2010 (20555325).


p = 0.024 by Surolia et al., but multiple hypotheses were tested (other variants in the same gene), and contradicted by Hunt et al.

See Surolia I et al. 2010 (20555325), Hunt KA et al. 2011 (22200769).

Familial -
Clinical importance
Severity 3

Autoimmune diseases have a wide range of effects.

Treatability 3

Can be treated with immunosuppressive drugs.

Penetrance 3

~6% attributable increased risk

See Surolia I et al. 2010 (20555325).



Moderate clinical importance, Uncertain pathogenic

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

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • C @ chr11:124530664: 4.0% (431/10758) in EVS
  • C @ chr11:124035873: 5.5% (7/128) in GET-Evidence
  • Frequency shown in summary reports: 4.0% (431/10758)


Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature. 2010 Jul 8;466(7303):243-7. Epub 2010 Jun 16. PubMed PMID: 20555325; PubMed Central PMCID: PMC2900412.

This paper implicates this polymorphism as potentially contributing to autoimmune diseases when homozygous. The variant was seen homozygously in 8 out of 923 cases and 0 out of 648 controls. Using two-tailed Fisher’s Exact, this is p = 0.024. However, because there are several other polymorphisms, multiple hypotheses were implicitly being tested and so we give this a case/control significance of 1 point (0.1 < p < 0.05). The overall allele frequency of the variant in controls is 0.049, they list four other variants with allele frequencies > 0.025.

They report that the protein product with this variant is catalytically active but is not secreted. This finding was reproduced in a pulse-chase experiment with 35S-methionine.

This data suggests homozygosity for this variant explains ~1% of autoimmune cases. An allele frequency of 0.049 implies that .24% of people are homozygous for this variant. Assuming an incidence of autoimmune disease in 1 out of 50 people, 0.02% of people would be expected to have autoimmune disease that might be attributed to this variant — this puts an estimate of penetrance for autoimmune disease in the homozygous individuals at ~8% (.02 / .24), approximately fourfold relative risk and ~6% attributable increased risk.

Hunt KA, Smyth DJ, Balschun T, Ban M, Mistry V, Ahmad T, Anand V, Barrett JC, Bhaw-Rosun L, Bockett NA, Brand OJ, Brouwer E, Concannon P, Cooper JD, Dias KR, van Diemen CC, Dubois PC, Edkins S, Fölster-Holst R, Fransen K, Glass DN, Heap GA, Hofmann S, Huizinga TW, Hunt S, Langford C, Lee J, Mansfield J, Marrosu MG, Mathew CG, Mein CA, Müller-Quernheim J, Nutland S, Onengut-Gumuscu S, Ouwehand W, Pearce K, Prescott NJ, Posthumus MD, Potter S, Rosati G, Sambrook J, Satsangi J, Schreiber S, Shtir C, Simmonds MJ, Sudman M, Thompson SD, Toes R, Trynka G, Vyse TJ, Walker NM, Weidinger S, Zhernakova A, Zoledziewska M; Type 1 Diabetes Genetics Consortium; UK Inflammatory Bowel Disease (IBD) Genetics Consortium; Wellcome Trust Case Control Consortium, Weersma RK, Gough SC, Sawcer S, Wijmenga C, Parkes M, Cucca F, Franke A, Deloukas P, Rich SS, Todd JA, van Heel DA. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry. Nat Genet. 2011 Dec 27;44(1):3-5. doi: 10.1038/ng.1037. PubMed PMID: 22200769; PubMed Central PMCID: PMC3287292.



hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr11:124530664


hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het C @ chr11:124530664


hu43860C - CGI sample GS00253-DNA_A01_200_37
het C @ chr11:124530664


hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr11:124530664


huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het C @ chr11:124530664


huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het C @ chr11:124530664


huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het C @ chr11:124530664


GS06994 - var-GS06994-1100-36-ASM
het C @ chr11:124035874


GS10851 - var-GS10851-1100-36-ASM
hom C @ chr11:124035874


Other external references

  • rs78778622
  • Score: 0.015 (benign)

Other in silico analyses

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 0

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Gene search

"GENE" or "GENE A123C":

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