ASCL1

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

Basic information

Region (hg38): 12:102957674-102960513

Links

ENSG00000139352 ∙ NCBI:429 ∙ OMIM:100790 ∙ HGNC:738 ∙ Uniprot:P50553 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Haddad syndrome (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Central hypoventilation syndrome, congenital (Haddad syndrome)	AD	Neurologic	Early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality	Neurologic	14532329

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ASCL1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ASCL1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				2	1	3
missense			12	1		13
nonsense						0
start loss						0
frameshift						0
inframe indel			1	6	4	11
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding					1	1
Total	0	0	13	9	6

Variants in ASCL1

This is a list of pathogenic ClinVar variants found in the ASCL1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-102958048-T-C			Benign (Nov 10, 2018)
12-102958291-C-A		not specified	Uncertain significance (May 27, 2022)
12-102958295-G-T		not specified	Uncertain significance (Apr 20, 2024)
12-102958296-C-A		Congenital central hypoventilation	Uncertain significance (Dec 01, 2003)
12-102958344-ACGGCCGCAGCCGCGG-A		Congenital central hypoventilation	Uncertain significance (Dec 01, 2003)
12-102958345-C-G			Uncertain significance (Jun 01, 2023)
12-102958346-GGCCGCAGCCGCG-C			Uncertain significance (Jan 05, 2024)
12-102958346-GGCCGCAGCCGCGGCGGCCGCA-G		ASCL1-related disorder	Likely benign (Jun 11, 2019)
12-102958346-GGCCGCAGCCGCGGCGGCCGCAGCC-G		Haddad syndrome	Uncertain significance (Dec 01, 2003)
12-102958365-G-T		Hereditary cancer	Likely benign (Jan 23, 2024)
12-102958367-A-G		not specified • ASCL1-related disorder	Benign/Likely benign (Jan 01, 2023)
12-102958371-G-A		not specified	Uncertain significance (Nov 17, 2022)
12-102958378-C-T		not specified	Uncertain significance (Jul 25, 2023)
12-102958382-A-T		not specified	Likely benign (Dec 01, 2023)
12-102958393-CGCA-C		not specified	Likely benign (Sep 25, 2014)
12-102958393-CGCAGCA-C		not specified	Benign (May 04, 2022)
12-102958393-CGCAGCAGCA-C		not specified	Benign (Sep 01, 2022)
12-102958393-CGCAGCAGCAGCA-C		ASCL1-related disorder • Phenylketonuria	Likely benign (Jan 06, 2022)
12-102958393-CGCAGCAGCAGCAGCA-C		not specified • ASCL1-related disorder	Likely benign (Jan 22, 2015)
12-102958393-CGCAGCAGCAGCAGCAGCAGCAGCA-C		not specified • ASCL1-related disorder	Likely benign (Jun 14, 2018)
12-102958393-C-CGCA		not specified • Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	Benign (Dec 12, 2023)
12-102958393-C-CGCAGCA		not specified	Benign/Likely benign (Sep 25, 2014)
12-102958393-C-CGCAGCAGCA		not specified	Benign (May 13, 2021)
12-102958393-C-CGCAGCAGCAGCA		not specified • ASCL1-related disorder	Conflicting classifications of pathogenicity (Sep 14, 2015)
12-102958393-C-CGCAGCAGCAGCAGCAGCAGCAGCAGCA		ASCL1-related disorder	Likely benign (May 24, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ASCL1	protein_coding	protein_coding	ENST00000266744	1	2831

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.677	0.319	124869	0	1	124870	0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.58	75	125	0.601	0.00000565	1489
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000888	0.00000888
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Neural Crest Differentiation;Dopaminergic Neurogenesis;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Notch-mediated HES/HEY network (Consensus)

Recessive Scores

• pRec: 0.476

Haploinsufficiency Scores

• pHI: 0.856
• hipred: Y
• hipred_score: 0.745
• ghis: 0.590

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ascl1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; taste/olfaction phenotype; pigmentation phenotype; endocrine/exocrine gland phenotype; craniofacial phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: ascl1a
• Affected structure: Muller cell
• Phenotype tag: abnormal
• Phenotype quality: decreased occurrence

Gene ontology

• 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;Notch signaling pathway;regulation of mitotic cell cycle;neuroblast fate determination;neuroblast proliferation;sensory organ development;heart development;response to lithium ion;regulation of gene expression;oligodendrocyte development;spinal cord association neuron differentiation;spinal cord oligodendrocyte cell fate specification;vestibular nucleus development;cerebral cortex GABAergic interneuron differentiation;commitment of neuronal cell to specific neuron type in forebrain;central nervous system neuron development;cerebral cortex development;neurogenesis;neuron differentiation;regulation of epithelial cell differentiation;response to retinoic acid;negative regulation of apoptotic process;positive regulation of neuron apoptotic process;negative regulation of neuron differentiation;positive regulation of neuron differentiation;positive regulation of Notch signaling pathway;positive regulation of cell cycle;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;cell maturation;sympathetic nervous system development;neuron fate commitment;neuron fate specification;neuron development;regulation of neurogenesis;musculoskeletal movement, spinal reflex action;response to folic acid;subpallium neuron fate commitment;regulation of timing of subpallium neuron differentiation;olfactory pit development;lung epithelial cell differentiation;ventral spinal cord interneuron fate commitment;lung neuroendocrine cell differentiation;stomach neuroendocrine cell differentiation;carotid body glomus cell differentiation;adrenal chromaffin cell differentiation;sympathetic ganglion development;response to epidermal growth factor;cellular response to magnetism;positive regulation of neural precursor cell proliferation
• Cellular component: nucleus;neuronal cell body;RNA polymerase II transcription factor complex
• 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;DNA-binding transcription factor activity;protein binding;transcription factor binding;protein homodimerization activity;bHLH transcription factor binding;E-box binding