SIAH1

Chr 16AD

siah E3 ubiquitin protein ligase 1

Also known as: BURHAS, SIAH1A

NCBI Gene: 6477 ENSG00000196470 UniProt: Q8IUQ4

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]

Primary Disease Associations & Inheritance

Buratti-Harel syndromeMIM #619314

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

3.2

Missense Z· constrained

0.50

LOEUF

Clinical Summary— SIAH1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.70) — some intolerance to loss-of-function variants.

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ClinVar Variants

33 Pathogenic / Likely Pathogenic· 38 VUS of 80 total submissions

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.50LOEUF

pLI 0.699

Z-score 2.77

OE 0.16 (0.06–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.23Z-score

OE missense 0.33 (0.27–0.41)

61 obs / 184.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.06–0.50)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.33 (0.27–0.41)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15

0≤1.21.6

LoF obs/exp: 2 / 12.6Missense obs/exp: 61 / 184.3Syn Z: -1.00

0.4488th %ile

GOF

0.3689th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 18% of P/LP variants are LoF · LOEUF 0.50

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.