BHLHE41

protein-coding

basic helix-loop-helix family member e41, the group of Basic helix-loop-helix proteins

Gene summary

This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. Defects in this gene are associated with the short sleep phenotype. [provided by RefSeq, Feb 2014]

Previous symbols:

BHLHB3

MANE transcript

NM_030762.3

Inheritance

ClinVar variants

U:85B:21

Top phenotype

Short sleeper, familial natural, 1

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr12:26,120,030-26,125,037

External References & Databases

Ensembl (ENSG00000123095)

Transcript & Mutation Effects

hg38 • Region Span ~5.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short sleep, familial natural, 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020784

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Short sleeper, familial natural, 1AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19679812

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BHLHE41 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 93

not providedTotal: 10

BHLHE41-related disorderTotal: 7

Short sleep, familial natural, 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030762.3. 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				18 clinvar	1 clinvar	19
missense			85 clinvar	1 clinvar	1 clinvar	87
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	85	19	2	106

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030762.3	RefSeq	NP_110389.1	5	MANE Select
ENST00000242728.5	Ensembl	ENSP00000242728.4	5	MANE Select
ENST00000957109.1	Ensembl	ENSP00000627168.1	5	Standard
ENST00000957109.2	Ensembl	ENSP00000627168.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bhlhe41	Danio rerio	Structure: locomotion Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

bhlhe41

Danio rerio

Structure: locomotion

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Circadian rhythm - Homo sapiens (human)
NOTCH-Ncore
BMAL1-CLOCK,NPAS2 activates circadian gene expression
Pathways in clear cell renal cell carcinoma
Circadian Clock

Biological Process

negative regulation of transcription by RNA polymerase II
somitogenesis
Notch signaling pathway
cell population proliferation
animal organ morphogenesis

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II activating transcription factor binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000242728
Coding exons: 5
Length: 5102
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.823	158	190	0.832	0.00000888	2965
Missense (PolyPhen)		37	61.676	0.59991		832
Synonymous	-0.467	91	85.5	1.06	0.00000432	1031
Loss of Function	3.53	0	14.5	0.00	6.82e-7	200

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes. Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA/B/G, NR1H3/LXRA, NR1H4 and VDR transactivation activity. {ECO:0000269|PubMed:11278948, ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:15193144, ECO:0000269|PubMed:15560782, ECO:0000269|PubMed:18411297, ECO:0000269|PubMed:19786558}.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

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