SIRT5

protein-coding

sirtuin 5, the group of Sirtuins

Gene summary

This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class III of the sirtuin family. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2010]

MANE transcript

NM_012241.5

Inheritance

—

ClinVar variants

U:57B:5

Top phenotype

SIRT5-related disorder

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr6:13,574,227-13,615,158

External References & Databases

Ensembl (ENSG00000124523)

Transcript & Mutation Effects

hg38 • Region Span ~40.9 kb

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GenCC 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 SIRT5 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 55

not providedTotal: 1

SIRT5-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012241.5. 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			4 clinvar			4
missense			52 clinvar	5 clinvar		57
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	57	5	0	62

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 198 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012241.5	RefSeq	NP_036373.1	8	MANE Select
ENST00000606117.2	Ensembl	ENSP00000476228.1	8	MANE Select
NM_001193267.2	RefSeq	NP_001180196.1	7	Standard
NM_001242827.1	RefSeq	NP_001229756.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NAD+ metabolism
NAD+ biosynthetic pathways
Transcriptional activation of mitochondrial biogenesis
Mitochondrial biogenesis
Organelle biogenesis and maintenance

Biological Process

chromatin silencing
protein ADP-ribosylation
protein deacetylation
mitochondrion organization
regulation of ketone biosynthetic process

Molecular Function

NAD+ ADP-ribosyltransferase activity
zinc ion binding
NAD-dependent protein deacetylase activity
protein-malonyllysine demalonylase activity
protein-succinyllysine desuccinylase activity

Cellular Component

nucleus
mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000606117
Coding exons: 8
Length: 39975
Individuals with no LoFs: 125651
Homozygous LoFs: 0
Heterozygous LoFs: 97
Defined: 125748
p: 0.000386

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.140	188	194	0.972	0.0000118	1986
Missense (PolyPhen)		67	65.854	1.0174		655
Synonymous	-0.329	75	71.5	1.05	0.00000423	645
Loss of Function	0.769	16	19.7	0.813	0.00000140	187

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.0010	0.0010	notable
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693, PubMed:29180469). Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062). Activates SHMT2 by mediating its desuccinylation (PubMed:29180469). Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity). Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX. {ECO:0000250|UniProtKB:Q8K2C6, ECO:0000269|PubMed:18680753, ECO:0000269|PubMed:21908771, ECO:0000269|PubMed:22076378, ECO:0000269|PubMed:24140062, ECO:0000269|PubMed:24703693, ECO:0000269|PubMed:29180469}.;

Recessive Scores

pRec: 0.162

Intolerance Scores

LoFtool: 0.957
RVIS EVS: 0.33
RVIS percentile EVS: 73.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.723

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium