GeneBe

SIAH1

protein-coding

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

Gene summary

This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in the development of certain forms of Parkinson's disease, the regulation of the cellular response to hypoxia and induction of apoptosis. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003031.4

Inheritance

AD

ClinVar variants

P:23U:35B:10

Top phenotype

Buratti-Harel syndrome

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr16:48,356,364-48,448,402

External References & Databases

Ensembl (ENSG00000196470)NCBI Gene (6477)OMIM (602212)HGNC:10857GenCCUniProt (Q8IUQ4)AlphaFoldClinVar (SIAH1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~92.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Buratti-Harel syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859144

Submitter: G2P

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Buratti-Harel syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859144

Submitter: Labcorp Genetics (formerly Invitae)

Buratti-Harel syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859144

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Buratti-Harel syndromeAD

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 28600779; 32430360Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIAH1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 30
Buratti-Harel syndromeTotal: 15
Inborn genetic diseasesTotal: 15
See casesTotal: 9
not specifiedTotal: 4
SIAH1-related conditionTotal: 4
Neurodevelopmental disorderTotal: 1
SIAH1-related neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003031.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
8
clinvar
2
clinvar
 11
missense
4
clinvar
9
clinvar
30
clinvar
 43
nonsense
2
clinvar
 2
start loss
1
clinvar
 1
frameshift
1
clinvar
7
clinvar
2
clinvar
 10
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total518358268
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003031.4RefSeqNP_003022.31MANE Select
ENST00000394725.3EnsemblENSP00000378214.21MANE Select
NM_001006610.2RefSeqNP_001006611.12Standard
ENST00000356721.3EnsemblENSP00000349156.32Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

Biological Process

  • protein polyubiquitination
  • ubiquitin-dependent protein catabolic process
  • apoptotic process
  • cell cycle
  • spermatogenesis

Molecular Function

  • ubiquitin-protein transferase activity
  • protein binding
  • protein C-terminus binding
  • zinc ion binding
  • ubiquitin conjugating enzyme binding

Cellular Component

  • nucleus
  • cytoplasm
  • early endosome
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000356721
Coding exons
2
Length
92039
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125748
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.23611840.3310.000009972052
Missense (PolyPhen)765.5770.10674777
Synonymous-1.007867.51.150.00000380634
Loss of Function2.77212.60.1588.70e-7123

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000980.000098rare
Other0.000160.00016rare

dbNSFP Gene Annotations

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}.;

Intolerance Scores

LoFtool
0.574
RVIS EVS
0.13
RVIS percentile EVS
62.74

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.633

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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