ASCL1

protein-coding

achaete-scute family bHLH transcription factor 1, the group of Basic helix-loop-helix proteins

Gene summary

This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004316.4

Inheritance

AD, AR

ClinVar variants

U:34B:11

Top phenotype

Central hypoventilation syndrome, congenital (Haddad syndrome)

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr12:102,957,674-102,960,513

External References & Databases

Ensembl (ENSG00000139352)

Transcript & Mutation Effects

hg38 • Region Span ~2.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

central hypoventilation syndrome, congenital, 1, with or without Hirschsprung diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0800026

Submitter: PanelApp Australia

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

Haddad syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020493

Submitter: Orphanet

Clinical Genomic Database (CGD)

Central hypoventilation syndrome, congenital (Haddad syndrome)AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality

Refs: 14532329

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASCL1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 44

ASCL1-related disorderTotal: 16

not providedTotal: 11

Haddad syndromeTotal: 2

Congenital central hypoventilationTotal: 2

PhenylketonuriaTotal: 1

Hereditary cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004316.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				9 clinvar		9
missense			34 clinvar	2 clinvar		36
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	34	11	0	45

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004316.4	RefSeq	NP_004307.2	1	MANE Select
ENST00000266744.4	Ensembl	ENSP00000266744.3	1	MANE Select
ENST00001135113.1	Ensembl	ENSP00000803868.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ascl1a	Danio rerio	Structure: Muller cell Quality: decreased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

ascl1a

Danio rerio

Structure: Muller cell

Quality: decreased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neural Crest Differentiation
Dopaminergic Neurogenesis
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Notch-mediated HES/HEY network

Biological Process

negative regulation of transcription by RNA polymerase II
neuron migration
noradrenergic neuron development
noradrenergic neuron fate commitment
regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
chromatin binding

Cellular Component

nucleus
neuronal cell body
RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266744
Coding exons: 1
Length: 2831
Individuals with no LoFs: 124869
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124870
p: 0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.58	75	125	0.601	0.00000565	1489
Missense (PolyPhen)		11	47.652	0.23084		470
Synonymous	-0.271	61	58.4	1.05	0.00000288	483
Loss of Function	2.29	1	7.97	0.125	3.45e-7	83

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000089	0.0000089	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways. Directly binds the E box motif (5'-CANNTG-3') on promoters and promotes transcription of neuronal genes. The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro. Plays a role at early stages of development of specific neural lineages in most regions of the CNS, and of several lineages in the PNS. Essential for the generation of olfactory and autonomic neurons. Acts synergistically with FOXN4 to specify the identity of V2b neurons rather than V2a from bipotential p2 progenitors during spinal cord neurogenesis, probably through DLL4-NOTCH signaling activation. {ECO:0000250|UniProtKB:Q02067}.;

Recessive Scores

pRec: 0.476

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium