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UniProtKB/Swiss-Prot Q9Y6K9: Variant p.Cys417Arg

NF-kappa-B essential modulator
Variant information

Variant position:  417
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Cysteine (C) to Arginine (R) at position 417 (C417R, p.Cys417Arg).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and polar (C) to large size and basic (R)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Variant description:  In EDAID1; loss of sumoylation.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  417
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  419
The length of the canonical sequence.

Location on the sequence:   CPKCQYQAPDMDTLQIHVME  C IE
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         CPKCQYQAPDMDTLQIHVMECIE--

Mouse                         CPKCQYQAPDMDTLQIHVMECIE

Rat                           CPKCQYQAPDMDTLQIHVMECIE

Pig                           CPKCQYQAPDMDTLQIHVMECIE

Bovine                        CPKCQYQAPDIDTLQIHVMECIE

Drosophila                    CPICSKSFNALSVLQSHVNDCLD

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

Chain 1 – 419 NF-kappa-B essential modulator
Zinc finger 389 – 419 CCHC NOA-type
Region 251 – 419 Required for interaction with TNFAIP3
Region 382 – 419 Interaction with CYLD
Cross 399 – 399 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 399 – 399 K -> R. Abolishes BCL10-mediated but not RIPK2-mediated ubiquitination. Important decrease in the ubiquitination level; when associated with R-285. No change in the ubiquitination level; when associated with R-115 or R-224.
Mutagenesis 414 – 414 V -> S. Abolishes binding to polyubiquitin.
Mutagenesis 415 – 415 M -> S. Impairs binding to polyubiquitin.

Literature citations

Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress.
Huang T.T.; Wuerzberger-Davis S.M.; Wu Z.H.; Miyamoto S.;
Cell 115:565-576(2003)

A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).
Zonana J.; Elder M.E.; Schneider L.C.; Orlow S.J.; Moss C.; Golabi M.; Shapira S.K.; Farndon P.A.; Wara D.W.; Emmal S.A.; Ferguson B.M.;
Am. J. Hum. Genet. 67:1555-1562(2000)
Cited for: VARIANTS EDAID1 ARG-417 AND PHE-417;

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa B signaling.
Doeffinger R.; Smahi A.; Bessia C.; Geissmann F.; Feinberg J.; Durandy A.; Bodemer C.; Kenwrick S.J.; Dupuis-Girod S.; Blanche S.; Wood P.; Rabia S.H.; Headon D.J.; Overbeek P.A.; Le Deist F.; Holland S.M.; Belani K.; Kumararatne D.S.; Fischer A.; Shapiro R.; Conley M.E.; Reimund E.; Kalhoff H.; Abinun M.; Munnich A.; Israael A.; Courtois G.; Casanova J.-L.;
Nat. Genet. 27:277-285(2001)
Cited for: INVOLVEMENT IN EDAID1; VARIANTS EDAID1 PRO-175; PRO-227; GLY-288; ASN-311; ARG-417 AND PHE-417;

Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia.
Jain A.; Ma C.A.; Liu S.; Brown M.; Cohen J.; Strober W.;
Nat. Immunol. 2:223-228(2001)
Cited for: VARIANTS EDAID1 VAL-406 AND ARG-417;

Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.
Orange J.S.; Brodeur S.R.; Jain A.; Bonilla F.A.; Schneider L.C.; Kretschmer R.; Nurko S.; Rasmussen W.L.; Koehler J.R.; Gellis S.E.; Ferguson B.M.; Strominger J.L.; Zonana J.; Ramesh N.; Ballas Z.K.; Geha R.S.;
J. Clin. Invest. 109:1501-1509(2002)
Cited for: VARIANTS EDAID1 ARG-153 AND ARG-417;

The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation.
Orange J.S.; Jain A.; Ballas Z.K.; Schneider L.C.; Geha R.S.; Bonilla F.A.;
J. Allergy Clin. Immunol. 113:725-733(2004)

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.