SIRT6
protein-codingsirtuin 6, the group of Sirtuins
Gene summary
This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SIRT6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016539.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 6 | 7 | |||
| missense | 2 | 59 | 5 | 1 | 67 | |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 2 | 64 | 11 | 1 | 78 |
Highest pathogenic variant AF is 0.000008685176
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057623.2 | 8 | MANE Select | |
| Ensembl | ENSP00000337332.1 | 8 | MANE Select | |
| RefSeq | NP_001180214.1 | 7 | Standard | |
| RefSeq | NP_001307987.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Central carbon metabolism in cancer - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
- SREBF and miR33 in cholesterol and lipid homeostasis
- NAD+ metabolism
- NAD+ biosynthetic pathways
Biological Process
- post-embryonic cardiac muscle cell growth involved in heart morphogenesis
- base-excision repair
- protein ADP-ribosylation
- negative regulation of cell population proliferation
- regulation of double-strand break repair via homologous recombination
Molecular Function
- chromatin binding
- transcription corepressor activity
- NAD+ ADP-ribosyltransferase activity
- NAD(P)+-protein-arginine ADP-ribosyltransferase activity
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- nuclear telomeric heterochromatin
- nucleolus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000337491
- Coding exons
- 8
- Length
- 8496
- Individuals with no LoFs
- 125706
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125717
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.605 | 190 | 215 | 0.884 | 0.0000145 | 2212 |
| Missense (PolyPhen) | 65 | 87.935 | 0.73918 | 866 | ||
| Synonymous | 0.401 | 94 | 99.1 | 0.949 | 0.00000736 | 760 |
| Loss of Function | 2.40 | 5 | 15.1 | 0.332 | 9.21e-7 | 147 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00030 | 0.00025 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00018 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: NAD-dependent protein deacetylase. Has deacetylase activity towards histone H3K9Ac and H3K56Ac. Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle. Deacetylates histone H3K9Ac at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF- kappa-B target genes. Acts as a corepressor of the transcription factor HIF1A to control the expression of multiple glycolytic genes to regulate glucose homeostasis. Required for genomic stability. Regulates the production of TNF protein. Has a role in the regulation of life span (By similarity). Deacetylation of nucleosomes interferes with RELA binding to target DNA. May be required for the association of WRN with telomeres during S-phase and for normal telomere maintenance. Required for genomic stability. Required for normal IGF1 serum levels and normal glucose homeostasis. Modulates cellular senescence and apoptosis. On DNA damage, promotes DNA end resection via deacetylation of RBBP8. Has very weak deacetylase activity and can bind NAD(+) in the absence of acetylated substrate. {ECO:0000250, ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:19625767, ECO:0000269|PubMed:20829486, ECO:0000269|PubMed:21362626}.;
Recessive Scores
- pRec
- 0.175
Intolerance Scores
- LoFtool
- 0.505
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |