NACC1

Chr 19AD

nucleus accumbens associated 1

Also known as: BEND8, BTBD14B, BTBD30, NAC-1, NAC1, NECFM

NCBI Gene: 112939 ENSG00000160877 UniProt: Q96RE7

This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Feb 2012]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelinationMIM #617393

536

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— NACC1

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Gene-Disease Validity (ClinGen)

NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

29 Pathogenic / Likely Pathogenic· 215 VUS of 536 total submissions

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

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.

0.17LOEUF

pLI 0.998

Z-score 3.90

OE 0.00 (0.00–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% 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.

4.17Z-score

OE missense 0.39 (0.34–0.45)

143 obs / 367.9 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.0.00 (0.00–0.17)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.39 (0.34–0.45)

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.0.97

0≤1.21.6

LoF obs/exp: 0 / 17.7Missense obs/exp: 143 / 367.9Syn Z: 0.35