SIRT4

sirtuin 4, the group of Sirtuins

Basic information

Region (hg38): 12:120302316-120313249

Links

ENSG00000089163 ∙ NCBI:23409 ∙ OMIM:604482 ∙ HGNC:14932 ∙ Uniprot:Q9Y6E7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SIRT4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIRT4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					1	1
missense			22	2	1	25
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	22	2	2

Variants in SIRT4

This is a list of pathogenic ClinVar variants found in the SIRT4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-120303624-C-G		not specified	Uncertain significance (Oct 10, 2023)
12-120303647-T-C		not specified	Likely benign (May 16, 2024)
12-120303767-C-T		not specified	Uncertain significance (Sep 12, 2023)
12-120303812-G-T		not specified	Uncertain significance (Oct 26, 2021)
12-120303850-C-T		not specified	Uncertain significance (Jun 02, 2023)
12-120303865-C-T			Benign (Mar 02, 2018)
12-120303866-G-A		not specified	Uncertain significance (Jun 24, 2022)
12-120303881-C-T		not specified	Uncertain significance (Nov 15, 2021)
12-120303955-G-A		not specified	Uncertain significance (Oct 12, 2021)
12-120303964-G-A		not specified	Uncertain significance (Dec 06, 2022)
12-120304016-C-T		not specified	Uncertain significance (Jul 26, 2022)
12-120304025-G-A		not specified	Likely benign (Jan 10, 2023)
12-120304052-T-A		not specified	Uncertain significance (Jun 24, 2022)
12-120312472-T-G		not specified	Uncertain significance (Mar 04, 2024)
12-120312482-A-C		not specified	Uncertain significance (Dec 02, 2022)
12-120312508-C-T		not specified	Uncertain significance (Mar 01, 2023)
12-120312571-G-A			Likely benign (Dec 01, 2022)
12-120312577-C-G		not specified	Uncertain significance (Aug 13, 2021)
12-120312648-T-G		not specified	Uncertain significance (Mar 07, 2023)
12-120312713-A-C		not specified	Uncertain significance (May 24, 2023)
12-120312718-G-A		not specified	Uncertain significance (May 29, 2024)
12-120312897-A-C		not specified	Uncertain significance (May 30, 2023)
12-120312926-A-C		not specified	Uncertain significance (Sep 22, 2022)
12-120312936-T-C		not specified	Uncertain significance (Sep 26, 2023)
12-120312943-A-T			Benign (Mar 02, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIRT4	protein_coding	protein_coding	ENST00000202967	3	10934

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.86e-10	0.0389	125691	0	56	125747	0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.01	158	198	0.797	0.0000124	2033
Missense in Polyphen		58	73.518	0.78892		759
Synonymous	0.816	69	78.2	0.883	0.00000475	652
Loss of Function	-0.518	13	11.1	1.17	4.74e-7	129

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000662	0.000662
Ashkenazi Jewish	0.00	0.00
East Asian	0.000435	0.000435
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000969	0.0000967
Middle Eastern	0.000435	0.000435
South Asian	0.000653	0.000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as NAD-dependent protein lipoamidase, ADP-ribosyl transferase and deacetylase. Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP- ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD- dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1:PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin secretion. {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000269|PubMed:16959573, ECO:0000269|PubMed:17715127, ECO:0000269|PubMed:23438705, ECO:0000269|PubMed:23562301, ECO:0000269|PubMed:23663782, ECO:0000269|PubMed:24043310, ECO:0000269|PubMed:25525879}.
• Pathway: NAD+ metabolism;NAD+ biosynthetic pathways;Transcriptional activation of mitochondrial biogenesis;Mitochondrial biogenesis;Organelle biogenesis and maintenance (Consensus)

Intolerance Scores

• loftool: 0.968
• rvis_EVS: -0.09
• rvis_percentile_EVS: 46.92

Haploinsufficiency Scores

• pHI: 0.150
• hipred: N
• hipred_score: 0.255
• ghis: 0.483

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.931

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sirt4
• Phenotype: homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal phenotype; skeleton phenotype

Gene ontology

• Biological process: regulation of glutamine family amino acid metabolic process;chromatin silencing;protein ADP-ribosylation;glutamine metabolic process;cellular response to DNA damage stimulus;mitochondrion organization;negative regulation of cardiac muscle cell apoptotic process;peptidyl-lysine deacetylation;negative regulation of fatty acid oxidation;negative regulation of insulin secretion;positive regulation of lipid biosynthetic process;cellular response to hypoxia;tricarboxylic acid metabolic process;negative regulation of protein processing involved in protein targeting to mitochondrion;regulation of pyruvate dehydrogenase activity
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial matrix
• Molecular function: NAD+ ADP-ribosyltransferase activity;protein binding;zinc ion binding;NAD-dependent protein deacetylase activity;biotinidase activity;lipoamidase activity;NAD+ binding