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UniProtKB/Swiss-Prot O14746: Variant p.His412Tyr

Telomerase reverse transcriptase
Gene: TERT
Chromosomal location: 5p15.33
Variant information

Variant position:  412
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
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 Histidine (H) to Tyrosine (Y) at position 412 (H412Y, p.His412Tyr).
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 (H) to large size and aromatic (Y)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  2
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:  Aplastic anemia (AA) [MIM:609135]: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia. {ECO:0000269|PubMed:15885610, ECO:0000269|PubMed:16627250, ECO:0000269|PubMed:16990594, ECO:0000269|PubMed:19760749}. Note=Disease susceptibility is associated with variations affecting 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.

Involvement in disease:  Dyskeratosis congenita, autosomal recessive, 4 (DKCB4) [MIM:613989]: A severe form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:16332973, ECO:0000269|PubMed:17785587, ECO:0000269|PubMed:18042801, ECO:0000269|PubMed:21602826}. Note=The disease is caused by mutations affecting 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.

Involvement in disease:  Pulmonary fibrosis, and/or bone marrow failure, telomere-related, 1 (PFBMFT1) [MIM:614742]: A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. {ECO:0000269|PubMed:15814878, ECO:0000269|PubMed:17460043, ECO:0000269|PubMed:21436073, ECO:0000269|PubMed:21483807, ECO:0000269|PubMed:22512499}. Note=The disease is caused by mutations affecting 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 PFBMFT1, AA and DKCB4; severe and moderate; associated with susceptibility to acute myelogenous leukemia; the mutant protein has 36% residual activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  412
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1132
The length of the canonical sequence.

Location on the sequence:   LFLELLGNHAQCPYGVLLKT  H CPLRAAVTPAAGVCAREKPQ
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                         LFLELLGNHAQCPYGVLLKTHCPLRAAVT---------PAAGVCAREKPQ

                              LFQELLGNHARCPYRALLRTHCPLRAMAAKEGSGNQAHRGV

Mouse                         LFQQLLVNHAECQYVRLLRSHCRFRTAN-------------

Rat                           LFQQLLMNHAKCQYVRFLRSHCRFRTAN-------------

Bovine                        LFRKLLGNHARSPYGALLRAHCPLPASAPRAGPDHQKCPGV

Baker's yeast                 TLQKLLKRHKRLNYVSILNSICPP-----------------

Fission yeast                 LIEQTAKRLHRISLSKVYNHYCPY-----------------

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 – 1132 Telomerase reverse transcriptase
Region 301 – 538 Required for oligomerization
Region 325 – 550 RNA-interacting domain 2
Region 376 – 521 QFP motif
Region 397 – 417 CP motif


Literature citations

Submission
NIEHS SNPs program;
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS TYR-412 AND THR-1062;

Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
Yamaguchi H.; Calado R.T.; Ly H.; Kajigaya S.; Baerlocher G.M.; Chanock S.J.; Lansdorp P.M.; Young N.S.;
N. Engl. J. Med. 352:1413-1424(2005)
Cited for: VARIANTS PFBMFT1 THR-202; TYR-412; MET-694; CYS-772 AND MET-1090; VARIANTS THR-279; GLU-441 DEL AND THR-1062;

Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.
Du H.Y.; Pumbo E.; Manley P.; Field J.J.; Bayliss S.J.; Wilson D.B.; Mason P.J.; Bessler M.;
Blood 111:1128-1130(2008)
Cited for: VARIANTS DKCB4 TYR-412 AND SER-704; CHARACTERIZATION OF VARIANTS DKCB4 TYR-412 AND SER-704;

Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia.
Kirwan M.; Vulliamy T.; Marrone A.; Walne A.J.; Beswick R.; Hillmen P.; Kelly R.; Stewart A.; Bowen D.; Schonland S.O.; Whittle A.M.; McVerry A.; Gilleece M.; Dokal I.;
Hum. Mutat. 30:1567-1573(2009)
Cited for: VARIANTS ALA-65; MET-299; LYS-522 AND THR-1062; VARIANTS AA THR-202; TYR-412; GLU-441 DEL; ASN-570; GLN-631; MET-694 AND LEU-785;

Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia.
Calado R.T.; Regal J.A.; Hills M.; Yewdell W.T.; Dalmazzo L.F.; Zago M.A.; Lansdorp P.M.; Hogge D.; Chanock S.J.; Estey E.H.; Falcao R.P.; Young N.S.;
Proc. Natl. Acad. Sci. U.S.A. 106:1187-1192(2009)
Cited for: VARIANTS ALA-65; MET-299; TYR-412; GLU-441 DEL; LYS-522 AND THR-1062;

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.