SIAH1

siah E3 ubiquitin protein ligase 1, the group of Ring finger proteins

Basic information

Region (hg38): 16:48356363-48448402

Links

ENSG00000196470 ∙ NCBI:6477 ∙ OMIM:602212 ∙ HGNC:10857 ∙ Uniprot:Q8IUQ4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complex neurodevelopmental disorder (Moderate), mode of inheritance: AD
• Buratti-Harel syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Buratti-Harel syndrome	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic	28600779; 32430360

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SIAH1 gene.

• not provided (15 variants)
• Buratti-Harel syndrome (4 variants)
• Inborn genetic diseases (2 variants)
• Neurodevelopmental disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIAH1 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				2	4	6
missense		4	8			12
nonsense						0
start loss						0
frameshift			2			2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			1			1
Total	0	4	11	2	4

Variants in SIAH1

This is a list of pathogenic ClinVar variants found in the SIAH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-48361616-G-A			Benign (Mar 30, 2018)
16-48361712-A-C			Likely benign (Nov 01, 2023)
16-48361731-C-T			Uncertain significance (Apr 25, 2022)
16-48361775-A-T			Benign (Aug 11, 2018)
16-48361860-A-G			Uncertain significance (Apr 01, 2022)
16-48361865-G-A			Benign (Aug 11, 2018)
16-48361900-C-G			Uncertain significance (Dec 01, 2023)
16-48361909-C-G		Buratti-Harel syndrome	Pathogenic (May 13, 2021)
16-48361909-C-T		Buratti-Harel syndrome	Uncertain significance (Sep 14, 2022)
16-48361927-T-C		Buratti-Harel syndrome	Pathogenic (May 13, 2021)
16-48361945-C-T		Buratti-Harel syndrome	Likely pathogenic (May 04, 2022)
16-48361974-T-C			Likely pathogenic (Oct 18, 2022)
16-48362046-C-A		Buratti-Harel syndrome	Pathogenic (May 13, 2021)
16-48362067-C-CA		Buratti-Harel syndrome	Likely pathogenic (Nov 23, 2022)
16-48362196-G-A			Uncertain significance (Mar 22, 2023)
16-48362203-G-A			Likely pathogenic (Apr 21, 2022)
16-48362224-G-C		Inborn genetic diseases	Uncertain significance (Sep 27, 2023)
16-48362279-C-T			Benign (Mar 30, 2018)
16-48362280-G-A		Buratti-Harel syndrome • Neurodevelopmental disorder	Likely pathogenic (Sep 14, 2021)
16-48362308-A-C		Buratti-Harel syndrome	Pathogenic (May 13, 2021)
16-48362321-C-T			Likely benign (Mar 01, 2023)
16-48362358-G-GC			Uncertain significance (Mar 21, 2023)
16-48362366-C-A			Uncertain significance (Mar 22, 2023)
16-48362380-G-C		Inborn genetic diseases	Uncertain significance (Oct 03, 2022)
16-48362394-C-T		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIAH1	protein_coding	protein_coding	ENST00000356721	2	92039

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.699	0.301	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.23	61	184	0.331	0.00000997	2052
Missense in Polyphen		7	65.577	0.10674		777
Synonymous	-1.00	78	67.5	1.15	0.00000380	634
Loss of Function	2.77	2	12.6	0.158	8.70e-7	123

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.000109	0.000109
South Asian	0.0000981	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin- conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP. Confers constitutive instability to HIPK2 through proteasomal degradation. It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF-alpha signaling. Has some overlapping function with SIAH2. Induces apoptosis in cooperation with PEG3. Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S- nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus. GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins. {ECO:0000269|PubMed:10747903, ECO:0000269|PubMed:11146551, ECO:0000269|PubMed:11389839, ECO:0000269|PubMed:11389840, ECO:0000269|PubMed:11483517, ECO:0000269|PubMed:11483518, ECO:0000269|PubMed:11752454, ECO:0000269|PubMed:12072443, ECO:0000269|PubMed:14506261, ECO:0000269|PubMed:14645235, ECO:0000269|PubMed:14654780, ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:16085652, ECO:0000269|PubMed:18536714, ECO:0000269|PubMed:19224863, ECO:0000269|PubMed:20508617, ECO:0000269|PubMed:22483617, ECO:0000269|PubMed:9334332, ECO:0000269|PubMed:9858595}.
• Pathway: p53 signaling pathway - Homo sapiens (human);Ubiquitin mediated proteolysis - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Parkin-Ubiquitin Proteasomal System pathway;miRNA regulation of p53 pathway in prostate cancer;Developmental Biology;Metabolism of proteins;Immune System;Adaptive Immune System;Antigen processing: Ubiquitination & Proteasome degradation;Amyloid fiber formation;Class I MHC mediated antigen processing & presentation;Netrin-1 signaling;Axon guidance (Consensus)

Intolerance Scores

• loftool: 0.574
• rvis_EVS: 0.13
• rvis_percentile_EVS: 62.74

Haploinsufficiency Scores

• pHI: 0.927
• hipred: Y
• hipred_score: 0.756
• ghis: 0.404

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.633

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Siah1a
• Phenotype: growth/size/body region phenotype; endocrine/exocrine gland phenotype; liver/biliary system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: protein polyubiquitination;ubiquitin-dependent protein catabolic process;apoptotic process;cell cycle;spermatogenesis;nervous system development;axon guidance;anatomical structure morphogenesis;protein catabolic process;protein destabilization;positive regulation of apoptotic process;proteasome-mediated ubiquitin-dependent protein catabolic process;cellular protein metabolic process;neuron apoptotic process;negative regulation of netrin-activated signaling pathway;positive regulation of intrinsic apoptotic signaling pathway
• Cellular component: nucleus;cytoplasm;early endosome;cytosol;plasma membrane;beta-catenin destruction complex
• Molecular function: ubiquitin-protein transferase activity;protein binding;protein C-terminus binding;zinc ion binding;ubiquitin conjugating enzyme binding;identical protein binding;ubiquitin protein ligase activity