NELFB

Chr 9

negative elongation factor complex member B

Also known as: COBRA1, NELF-B

NCBI Gene: 25920 ENSG00000188986 UniProt: Q8WX92 OMIM: 611180

NELFB encodes an essential component of the negative elongation factor (NELF) complex that regulates RNA polymerase II transcriptional pausing and is critical for maintaining embryonic stem cell pluripotency and facilitating cell fate decisions during development. The gene is highly constrained against loss-of-function variants (LOEUF 0.603), but no specific Mendelian disorders have been definitively associated with NELFB mutations in humans to date.

OMIM ResearchSummary from RefSeq, UniProt

NELFB is a subunit of negative elongation factor (NELF), which also includes NELFA (WHSC2; MIM 606026), either NELFC or NELFD (TH1L; MIM 605297), and NELFE (RDBP; MIM 154040). NELF acts with DRB sensitivity-inducing factor (DSIF), a heterodimer of SPT4 (SUPT4H1; MIM 603555) and SPT5 (SUPT5H; MIM 602102), to cause transcriptional pausing of RNA polymerase II (see MIM 180660) (Narita et al., 2003 [PubMed 12612062]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— NELFB

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

79 VUS of 100 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.003

Z-score 3.09

OE 0.35 (0.21–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.66Z-score

OE missense 0.75 (0.68–0.83)

271 obs / 359.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.21–0.60)

0≤0.351.4

Missense OE?0.75 (0.68–0.83)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 9 / 26.0Missense obs/exp: 271 / 359.7Syn Z: -1.41

This gene — mechanism propensity

0.6455th %ile

GOF

0.6834th %ile

LOF

0.3454th %ile

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

GOFprediction above median

DNprediction 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.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

VUS79

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	79	0	79
Likely Benign	0	1	1
Benign	0	0	0
Total	79	1	80

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

99 pathogenic / likely-pathogenic (of 111) ClinVar copy-number / structural variants overlap NELFB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →