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UniProtKB/Swiss-Prot Q9BYW2: Variant p.Phe2505Leu

Histone-lysine N-methyltransferase SETD2
Gene: SETD2
Chromosomal location: 3p21.31
Variant information

Variant position:  2505
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Unclassified
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Phenylalanine (F) to Leucine (L) at position 2505 (F2505L, p.Phe2505Leu).
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 large size and aromatic (F) to medium size and hydrophobic (L)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
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

Involvement in disease:  Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16314571, ECO:0000269|PubMed:24509477}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In AML; Impairs interaction with hyperphosphorylated POLR2A; unknown pathological significance; somatic mutation.
Any additional useful information about the variant.



Sequence information

Variant position:  2505
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2564
The length of the canonical sequence.

Location on the sequence:   CLNPYRKPDCKVGRITTTED  F KHLARKLTHGVMNKELKYCK
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                         CLNPYRKPDCKVGRITTTEDFKHLARKLTHGVMNKELKYCK

Mouse                         CLNPYRKPDCKVGRITTTEDFKHLARKLTHGVMNKELKYCK

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.

TypePositionsDescription
Chain 1 – 2564 Histone-lysine N-methyltransferase SETD2
Region 2457 – 2564 Interaction with POLR2A
Alternative sequence 1573 – 2564 Missing. In isoform 3.
Alternative sequence 1715 – 2564 Missing. In isoform 2.
Mutagenesis 2506 – 2506 K -> A. Impairs interaction with hyperphosphorylated POLR2A.
Mutagenesis 2510 – 2510 R -> A. Impairs interaction with hyperphosphorylated POLR2A.
Mutagenesis 2514 – 2514 H -> A. Impairs interaction with hyperphosphorylated POLR2A.
Mutagenesis 2515 – 2515 G -> AT. Does not affect interaction with hyperphosphorylated POLR2A.
Helix 2502 – 2524


Literature citations

Identification of functional cooperative mutations of SETD2 in human acute leukemia.
Zhu X.; He F.; Zeng H.; Ling S.; Chen A.; Wang Y.; Yan X.; Wei W.; Pang Y.; Cheng H.; Hua C.; Zhang Y.; Yang X.; Lu X.; Cao L.; Hao L.; Dong L.; Zou W.; Wu J.; Li X.; Zheng S.; Yan J.; Zhou J.; Zhang L.; Mi S.; Wang X.; Zhang L.; Zou Y.; Chen Y.; Geng Z.; Wang J.; Zhou J.; Liu X.; Wang J.; Yuan W.; Huang G.; Cheng T.; Wang Q.F.;
Nat. Genet. 46:287-293(2014)
Cited for: INVOLVEMENT IN AML; INVOLVEMENT IN ALL; VARIANTS AML 70-ARG--GLU-2564 DEL; ASN-800; GLY-1397; SER-1804; TRP-2122; 2325-GLN--GLU-2564 DEL AND LEU-2505; VARIANTS ALL SER-226; ILE-761; ASN-1493; 1496-ARG--GLU-2564 DEL; GLN-1654; 2077-ARG--GLU-2564 DEL; ALA-2214 AND 2524-CYS--GLU-2564 DEL;

Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1.
Li M.; Phatnani H.P.; Guan Z.; Sage H.; Greenleaf A.L.; Zhou P.;
Proc. Natl. Acad. Sci. U.S.A. 102:17636-17641(2005)
Cited for: STRUCTURE BY NMR OF 2457-2564; INTERACTION WITH POLR2A; MUTAGENESIS OF ARG-2475; LYS-2476; GLN-2480; PHE-2481; VAL-2483; LYS-2506; ARG-2510; HIS-2514; GLY-2515; GLU-2528 AND GLU-2531; CHARACTERIZATION OF VARIANT AML LEU-2505;

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.