UniProtKB/SwissProt variant VAR

Variant information

Variant position:

704

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 Proline (P) to Serine (S) at position 704 (P704S, p.Pro704Ser).

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 hydrophobic (P) to small size and polar (S)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

-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

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.

Variant description:

In DKCB4; the mutant protein has 13% residual activity.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs199422297 [ dbSNP | Ensembl ]

Sequence information

Variant position:

704

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:

DDIHRAWRTFVLRVRAQDPP P ELYFVKVDVTGAYDTIPQDR

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                         DDIHRAWRTF---VLRVRAQDPPPELYFVKVDVTGAYDTIPQDR

                              DDIHRAWRTF---VLRIRAQNPAPQLYFVKVDVTGAYDALP

Mouse                         NDIYRTWRAF---VLRVRALDQTPRMYFVKADVTGAYDAIP

Rat                           SDSYRIWRTF---VLRVRALDQTPRMYFVKADVTGAYDAIP

Bovine                        DDIHRAWRAF---VLPLRARGPAPPLYFVKVDVVGAYDALP

Baker's yeast                 TQIADRIKEFKQRLLK-KFNNVLPELYFMKFDVKSCYDSIP

Fission yeast                 -EVYMKLLTFKKDLLKHRMFGR--KKYFVRIDIKSCYDRIK

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.

Type	Positions	Description
Chain	1 – 1132	Telomerase reverse transcriptase
Domain	605 – 935	Reverse transcriptase
Metal binding	712 – 712	Magnesium; catalytic
Modified residue	707 – 707	Phosphotyrosine; by SRC-type Tyr-kinases
Mutagenesis	707 – 707	Y -> F. Abolishes oxidative stress-induced phosphorylation and RAN binding. Impaired nuclear export and enhanced antiapoptotic activity against ROS-dependent apoptosis induction. Impaired interaction with PTPN11. No dephosphorylation by PTPN11.
Mutagenesis	712 – 712	D -> A. Loss of telomerase activity. In the absence of TR, no loss of binding to telomeric primers.

Literature citations

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;

Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.
Batista L.F.; Pech M.F.; Zhong F.L.; Nguyen H.N.; Xie K.T.; Zaug A.J.; Crary S.M.; Choi J.; Sebastiano V.; Cherry A.; Giri N.; Wernig M.; Alter B.P.; Cech T.R.; Savage S.A.; Reijo Pera R.A.; Artandi S.E.;
Nature 474:399-402(2011)
Cited for: VARIANT DKCB4 SER-704; VARIANT DKCA2 TRP-979; CHARACTERIZATION OF VARIANT DKCB4 SER-704; CHARACTERIZATION OF VARIANT DKCA2 TRP-979; CATALYTIC ACTIVITY;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot O14746: Variant p.Pro704Ser