UNC13D A59T - GET-Evidence

Curation:
Currentness:

UNC13D A59T

(UNC13D Ala59Thr)


Short summary

Probably benign. This variant was reported to cause haemophagocytic lymphohistiocytosis in a recessive manner, but its allele frequency is inconsistent with this hypothesis and so we evaluate it as a nonpathogenic polymorphism.

Variant evidence
Computational 1

Polyphen 2 predicts benign effect

Functional -
Case/Control 3

Allele frequency in 1000 Genomes and HapMap data implies that this is not a causal variant, as it is inconsistent with the rarity of the disease.

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr17:73839326: 1.7% (185/10758) in EVS
  • T @ chr17:71350920: 1.6% (2/128) in GET-Evidence
  • Frequency shown in summary reports: 1.7% (185/10758)

Publications
 

Santoro A, Cannella S, Bossi G, Gallo F, Trizzino A, Pende D, Dieli F, Bruno G, Stinchcombe JC, Micalizzi C, De Fusco C, Danesino C, Moretta L, Notarangelo LD, Griffiths GM, Aricò M. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. J Med Genet. 2006 Dec;43(12):953-60. Epub 2006 Jul 6. PubMed PMID: 16825436; PubMed Central PMCID: PMC2563207.

A screen of UNC13D mutations in 30 families with haemophagocytic lymphohistiocytosis and in whom causal PRF1 mutations had not been found. 15 families had mutations in this gene identified. This variant was seen twice, both times compound heterozygously.

Controls are not reported. If 1000 Genomes data (3 variants in 226 alleles) is used, this is case+: 2, case-: 58, control+: 3, control-: 223. This lacks significance.

It seems likely that this variant is actually a nonpathogenic polymorphism, as this disease is rare and the variant is not seen with any significantly increased incidence in Santoro et al’s observations.

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het T @ chr17:73839326

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
hom T @ chr17:73839326

 

Other external references
 

    dbSNP
  • rs9904366
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the UNC13D gene
    Familial Hemophagocytic Lymphohistiocytosis
    Familial Hemophagocytic Lymphohistiocytosis 3
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/UNC13D
    PolyPhen-2
  • Score: 0 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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