FANCI P55L - GET-Evidence

Curation:
Currentness:

FANCI P55L

(FANCI Pro55Leu)


Short summary

Probably benign.

Variant evidence
Computational -1

Various tools predict a disruptive effect:
BLOSUM100 predicts disruptive effect
PolyPhen: Probably damaging 0.996
SIFT: Affect protein function 0.00
GVGD: GV 0.00; GD 97.78; Class C65 (most likely to interfere with function)
Variant Effect Predictor (Ensembl ):
SIFT=tolerated(0.16);
PolyPhen=probably_damaging(0.996);
Condel=deleterious(0.975)
Mutation Tasting Prediction: Disease causing, P value: 0.964977; protein features (might be) affected.

Functional 2

Localization and ubiquination normal

See Smogorzewska A et al. 2007 (17412408).

Case/Control 5

Allele frequency inconsistent with pathogenic effect

See unpublished research (below).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

unknown

Summary of published research, and additional commentary

Prevalence of Fanconi Anemia is 1 in 360,000 based on a 1 in 300 carrier rate, based on GeneTests: http://www.ncbi.nlm.nih.gov/books/NBK1401/

This puts an estimated upper limit on any disease causing variant as having an allele frequency of around 1 in 300 (0.3%). Using the PGP + public genomes, we see 6 out of 128 random alleles with this variant — the chances of seeing a variant this many times if it has 0.3% allele frequency is 2.9 * 10^-5. This establishes the variant as highly significantly deviant from a severe pathogenic effect of Fanconi Anemia.

Allele frequency

  • T @ chr15:89803950: 5.1% (546/10758) in EVS
  • T @ chr15:87604953: 4.7% (6/128) in GET-Evidence
  • Frequency shown in summary reports: 5.1% (546/10758)

Publications
 

Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. Epub 2007 Apr 5. PubMed PMID: 17412408; PubMed Central PMCID: PMC2175179.

Studying a cell line from a patient with Fanconi anemia, BD0952, where the FANCI protein was expressed at full levels but not ubiquitinated. This cell line had two nonsynonymous mutations in FANCI that were candidates for being causal — P55L and R1285Q. They created constructs with neither, one of each, and both of these variants and functionally characterized them. P55L alone behaved as wildtype, while 1285Q or 55L+1285Q failed to be ubiquinated. This indicated 55L was a nonpathogenic polymorphism and 1285Q was the disease causing mutation.

Genomes
 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het T @ chr15:89803950

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het T @ chr15:89803950

 

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het T @ chr15:89803950

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het T @ chr15:89803950

 

 

 

hu7A4AD1 - CGI sample GS01669-DNA_C05 from PGP sample 42408046
het T @ chr15:89803950

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het T @ chr15:89803950

 

GS10851 - var-GS10851-1100-36-ASM
het T @ chr15:87604954

 

GS19669 - var-GS19669-1100-36-ASM
het T @ chr15:87604954

 

Other external references
 

    dbSNP
  • rs62020347
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    Web search results (16 hits -- see all)
  • Identification of the FANCI Protein, a Monoubiquitinated ...
    FANCI shares sequence similarity with FANCD2, likely evolving from a common ancestral ... wt FANCI or P55L FANCI, but not R1285Q or P55L-R1285Q FANCI mutants. ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Identification of the Fanconi anemia (FANC) I protein, a ...
    The FANCI protein associates with FANCD2 and together, as the FANCI-FANCD2 (ID) ... expression constructs containing P55L, R1285Q, and P55L&R1285Q substitutions. ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2175179/?tool=EBI
  • Prognostic, diagnostic, and cancer therapeutic uses of FANCI ...
    ... and cancer therapeutic uses of FANCI and FANCI modulating agents ... shows the localization of WT, P55L, R1285Q, and P55L, R1285Q mutant proteins in BD0952 ...
    www.faqs.org/patents/app/20090081237
  • ファンコニー貧血(FA)はスイスの小児科医Guido Fanconiによって報告された小児遺伝性疾患で、骨髄不全、高発がん ...
    最も注目すべき点はモノユビキチン化されるFANCD2のK561とFANCIのK523を含む領域に高い相同性がみられたことから、FANCIとFANCD2はパラログであると示唆された。 ... これらのことからFANCIのR1285の変異が病気の原因の変異であると考えられる.しかし、FANCI-P55Lを導入した細胞でも、MMC ...
    wwwsoc.nii.ac.jp/jrr/japanese/paper/paper2007_9.htm
  • Type III 98%
    ... CAMK2 (0.986) RSK (0.968) NEPPK 8595410 LIMD1 Q9UGP4 G415R 413 ... FANCI Q9NVI1 P55L 54 VAR_032689 MAPK (0.981) IKK (0.934) MAPK (0.981) FA, could be a polymorphism, no effect ...
    nih.go.kr/phosphovariant/html/family_whole/TypeIII_98.txt
  • Type II- 95%
    ... PROT ID Variant site Phosphorylation site SWISS-PROT variant ID Removed kinase ... STE (0.613) Polymorphism (dbSNP:rs6008684) FANCI Q9NVI1 P55L 54 VAR_032689 ...
    www.nih.go.kr/phosphovariant/html/group_whole/TypeII-_95.txt
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    il2.dp.ua/news.php?readmore=56

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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