BNIP3

Chr 10

BCL2 interacting protein 3

Also known as: HABON, NIP3

NCBI Gene: 664 ENSG00000176171 UniProt: Q12983 OMIM: 603293

This gene encodes a mitochondrial pro-apoptotic protein that induces cell death by overcoming BCL2 suppression and participates in mitochondrial quality control by facilitating degradation of damaged mitochondrial proteins. The gene shows very low constraint against loss-of-function variants (pLI near 0, LOEUF 1.46), suggesting loss of function is well-tolerated in the general population. No established Mendelian diseases have been definitively linked to BNIP3 mutations in the pediatric population.

OMIM ResearchSummary from RefSeq, UniProt

This gene is encodes a mitochondrial protein that contains a BH3 domain and acts as a pro-apoptotic factor. The encoded protein interacts with anti-apoptotic proteins, including the E1B 19 kDa protein and Bcl2. This gene is silenced in tumors by DNA methylation. [provided by RefSeq, Dec 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.46

Clinical Summary— BNIP3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.46LOEUF

pLI 0.000

Z-score 0.53

OE 0.82 (0.48–1.46)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.83Z-score

OE missense 0.78 (0.66–0.93)

90 obs / 114.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.48–1.46)

0≤0.351.4

Missense OE?0.78 (0.66–0.93)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 8 / 9.8Missense obs/exp: 90 / 114.9Syn Z: 0.30

This gene — mechanism propensity

0.77top 25%

GOF

0.6541th %ile

LOF

0.3744th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.