NACC1

Chr 19

nucleus accumbens associated 1

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

NCBI Gene: 112939 ENSG00000160877 UniProt: Q96RE7

The protein functions as a transcriptional repressor in neuronal cells through recruitment of histone deacetylases and is required for recruiting the proteasome from the nucleus to the cytoplasm and dendritic spines. Mutations cause autosomal dominant neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination. The gene is highly constrained against loss-of-function variants (pLI 0.998, LOEUF 0.169), indicating intolerance to protein-truncating mutations.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.17

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

6 unique Pathogenic / Likely Pathogenic· 206 VUS of 509 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.39 (0.34–0.45)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNACC1-related infantile epilepsy, cataracts, and profound developmental delayGOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.3094th %ile

LOF

0.83top 5%

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

LOFprediction above median · LOEUF 0.17

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

509 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic4

VUS206

Likely Benign217

Benign60

Conflicting16

Pathogenic

Likely Pathogenic

206

VUS

217

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	4	0	0	4
VUS	8	185	9	4	206
Likely Benign	0	13	38	166	217
Benign	0	32	11	17	60
Conflicting	—				16
Total	8	236	58	187	505

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap NACC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →