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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P57727: Variant p.Pro404Leu

Transmembrane protease serine 3
Gene: TMPRSS3
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Variant information Variant position: help 404 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help 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: help From Proline (P) to Leucine (L) at position 404 (P404L, p.Pro404Leu). 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: help Similar physico-chemical property. Both residues are medium size and hydrophobic. The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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: help In DFNB8; fails to undergo proteolytic cleavage and is unable to activate ENaC. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 404 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 454 The length of the canonical sequence.
Location on the sequence: help MLCAGYLTGGVDSCQGDSGG P LVCQERRLWKLVGATSFGIG 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         MLCAGYLTGGVDSCQGDSGGPLVCQERRLWKLVGATSFGIG

Mouse                         MLCAGYLKGGVDSCQGDSGGPLVCQERRLWKLVGATSFGIG

Sequence annotation in neighborhood: help 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.
TypePositionsDescription
Chain 1 – 454 Transmembrane protease serine 3
Topological domain 70 – 454 Extracellular
Domain 217 – 449 Peptidase S1
Active site 401 – 401 Charge relay system
Disulfide bond 338 – 407
Disulfide bond 397 – 425
Alternative sequence 294 – 454 Missing. In isoform T.
Alternative sequence 318 – 454 EMIQPVCLPNSEENFPDGKVCWTSGWGATEDGAGDASPVLNHAAVPLISNKICNHRDVYGGIISPSMLCAGYLTGGVDSCQGDSGGPLVCQERRLWKLVGATSFGIGCAEVNKPGVYTRVTSFLDWIHEQMERDLKT -> GTSGSLCGSAALPLFQEDLQLLIEAFL. In isoform D.
Mutagenesis 401 – 401 S -> A. Fails to undergo proteolytic cleavage and is unable to activate ENaC.



Literature citations
The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro.
Guipponi M.; Vuagniaux G.; Wattenhofer M.; Shibuya K.; Vazquez M.; Dougherty L.; Scamuffa N.; Guida E.; Okui M.; Rossier C.; Hancock M.; Buchet K.; Reymond A.; Hummler E.; Marzella P.L.; Kudoh J.; Shimizu N.; Scott H.S.; Antonarakis S.E.; Rossier B.C.;
Hum. Mol. Genet. 11:2829-2836(2002)
Cited for: SUBCELLULAR LOCATION; AUTOCATALYTIC CLEAVAGE; MUTAGENESIS OF SER-401; CHARACTERIZATION OF VARIANTS DFNB8 GLY-103; TRP-109; PHE-194; CYS-251; LEU-404 AND ARG-407; FUNCTION IN ENAC CLEAVAGE; Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non-syndromic autosomal recessive deafness.
Masmoudi S.; Antonarakis S.E.; Schwede T.; Ghorbel A.M.; Gratri M.; Pappasavas M.P.; Drira M.; Elgaied-Boulila A.; Wattenhofer M.; Rossier C.; Scott H.S.; Ayadi H.; Guipponi M.;
Hum. Mutat. 18:101-108(2001)
Cited for: VARIANTS DFNB8 CYS-251 AND LEU-404; A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein.
Wattenhofer M.; Sahin-Calapoglu N.; Andreasen D.; Kalay E.; Caylan R.; Braillard B.; Fowler-Jaeger N.; Reymond A.; Rossier B.C.; Karaguzel A.; Antonarakis S.E.;
Hum. Genet. 117:528-535(2005)
Cited for: VARIANTS DFNB8 LEU-216 AND LEU-404;
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.