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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q93009: Variant p.Met225Ile

Ubiquitin carboxyl-terminal hydrolase 7
Gene: USP7
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Variant information Variant position: help 225 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 Methionine (M) to Isoleucine (I) at position 225 (M225I, p.Met225Ile). 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 1 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 HAFOUS. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 225 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 1102 The length of the canonical sequence.
Location on the sequence: help WDSKKHTGYVGLKNQGATCY M NSLLQTLFFTNQLRKAVYMM 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                         WDSKKHTGYVGLKNQGATCYMN--------SLLQTLFFTNQLRKAVYMM

Mouse                         WDSKKHTGYVGLKNQGATCYMN--------SLLQTLFFTNQ

Rat                           WDSKKHTGYVGLKNQGATCYMN--------SLLQTLFFTNQ

Chicken                       WDSKKHTGYVGLKNQGATCYMN--------SLLQTLFFTNQ

Caenorhabditis elegans        WDSKRHTGCIGLRNQGATCYMN--------SILQSFYFTTG

Drosophila                    WDSKKHTGYVGLKNQGATCYMN--------SLLQTLYFTNS

Baker's yeast                 RPSVLLEDVPSIYHEDDTSFASLNPPFREITADRSVTHRKD

Fission yeast                 ----SLTKAPNVLKSNSSHFKK----------EKKSKHSSG
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 – 1102 Ubiquitin carboxyl-terminal hydrolase 7
Domain 214 – 521 USP
Active site 223 – 223 Nucleophile
Mutagenesis 223 – 223 C -> A. Complete loss of activity. Localized in the nucleus and does not inhibit FOXO4-dependent transcriptional activity. Loss of ability to deubiquitinate CRY2.
Mutagenesis 223 – 223 C -> S. Catalytically inactive mutant. No effect on p53/TP53 and PTEN binding but is defective in deubiquitinating p53/TP53 and PTEN. Partial loss of KMT2E/mml5 deubiquitination. Decreases deubiquitinase activity toward 'Lys-48'-polyubiquitinated ALKBH3. Reduced deubiquitination of REST. Reduced deubiquitination of TRIM27 and WASHC1.
Helix 225 – 233



Literature citations
Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.
Fountain M.D.; Oleson D.S.; Rech M.E.; Segebrecht L.; Hunter J.V.; McCarthy J.M.; Lupo P.J.; Holtgrewe M.; Moran R.; Rosenfeld J.A.; Isidor B.; Le Caignec C.; Saenz M.S.; Pedersen R.C.; Morgan T.M.; Pfotenhauer J.P.; Xia F.; Bi W.; Kang S.L.; Patel A.; Krantz I.D.; Raible S.E.; Smith W.; Cristian I.; Torti E.; Juusola J.; Millan F.; Wentzensen I.M.; Person R.E.; Kuery S.; Bezieau S.; Uguen K.; Ferec C.; Munnich A.; van Haelst M.; Lichtenbelt K.D.; van Gassen K.; Hagelstrom T.; Chawla A.; Perry D.L.; Taft R.J.; Jones M.; Masser-Frye D.; Dyment D.; Venkateswaran S.; Li C.; Escobar L.F.; Horn D.; Spillmann R.C.; Pena L.; Wierzba J.; Strom T.M.; Parenti I.; Kaiser F.J.; Ehmke N.; Schaaf C.P.;
Genet. Med. 21:1797-1807(2019)
Cited for: VARIANTS HAFOUS ILE-225; LYS-345; PHE-373; ASP-392; GLY-485; 576-CYS--ASN-1102 DEL; PRO-757; THR-766 AND ASN-1080; INVOLVEMENT IN HAFOUS;
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.