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UniProtKB/Swiss-Prot Q8N6T7: Variant p.Asp63His

NAD-dependent protein deacylase sirtuin-6
Gene: SIRT6
Variant information

Variant position:  63
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  US
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:  From Aspartate (D) to Histidine (H) at position 63 (D63H, p.Asp63His).
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 acidic (D) to medium size and polar (H)
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

Variant description:  Found in a family presenting with four cases of perinatal lethality caused by severe neurodevelopmental and cardiac anomalies; abolished histone deacetylase activity; abolished protein demyristoylase activity; decreased ability to recognize and bind double-strand breaks (DSBs) sites; does not affect nuclear localization.
Any additional useful information about the variant.



Sequence information

Variant position:  63
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  355
The length of the canonical sequence.

Location on the sequence:   QSSSVVFHTGAGISTASGIP  D FRGPHGVWTMEERGLAPKFD
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                         QSSSVVFHTGAGISTASGIPDFRGPHGVWTMEERGLAPKFD

Mouse                         QSSSVVFHTGAGISTASGIPDFRGPHGVWTMEERGLAPKFD

Drosophila                    KSGHVVLHTGAGISTSAGIPDFRGPKGVWTLEEKGEKPDFN

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 2 – 355 NAD-dependent protein deacylase sirtuin-6
Domain 35 – 274 Deacetylase sirtuin-type
Binding site 53 – 53
Binding site 57 – 57
Binding site 64 – 64
Binding site 65 – 65
Binding site 71 – 71
Mutagenesis 45 – 45 S -> A. In AAA mutant; strongly decreased nucleosome-binding; when associated with 206-A--A-208.
Mutagenesis 56 – 56 S -> Y. Abolished NAD-dependent protein deacetylase, defatty-acylase and mono-ADP-ribosyltransferase activities.
Mutagenesis 60 – 60 G -> A. Does not affect the NAD-dependent protein defatty-acylase activity. Abolished NAD-dependent protein deacetylase and mono-ADP-ribosyltransferase activities.
Mutagenesis 65 – 65 R -> A. Does not affect the mono-ADP-ribosyltransferase activity. Abolished NAD-dependent protein deacetylase and defatty-acylase activities.
Mutagenesis 82 – 82 F -> AE. Reduced MDL-800 and MDL-801 compounds-binding.


Literature citations

SIRT6 is a DNA double-strand break sensor.
Onn L.; Portillo M.; Ilic S.; Cleitman G.; Stein D.; Kaluski S.; Shirat I.; Slobodnik Z.; Einav M.; Erdel F.; Akabayov B.; Toiber D.;
Elife 9:0-0(2020)
Cited for: FUNCTION; SUBCELLULAR LOCATION; SUBUNIT; MUTAGENESIS OF ALA-13 AND HIS-133; CHARACTERIZATION OF VARIANTS HIS-63 AND TYR-63;

An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.
Ferrer C.M.; Alders M.; Postma A.V.; Park S.; Klein M.A.; Cetinbas M.; Pajkrt E.; Glas A.; van Koningsbruggen S.; Christoffels V.M.; Mannens M.M.A.M.; Knegt L.; Etchegaray J.P.; Sadreyev R.I.; Denu J.M.; Mostoslavsky G.; van Maarle M.C.; Mostoslavsky R.;
Genes Dev. 32:373-388(2018)
Cited for: VARIANT HIS-63; CHARACTERIZATION OF VARIANT HIS-63; FUNCTION; SUBCELLULAR LOCATION; CATALYTIC ACTIVITY;

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.