SREBF1

protein-coding

sterol regulatory element binding transcription factor 1, the group of Basic helix-loop-helix proteins|MicroRNA protein coding host genes

Gene summary

This gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor that binds to the sterol regulatory element-1 (SRE1), which is a motif that is found in the promoter of the low density lipoprotein receptor gene and other genes involved in sterol biosynthesis. The encoded protein is synthesized as a precursor that is initially attached to the nuclear membrane and endoplasmic reticulum. Following cleavage, the mature protein translocates to the nucleus and activates transcription. This cleaveage is inhibited by sterols. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternative promoter usage and splicing result in multiple transcript variants, including SREBP-1a and SREBP-1c, which correspond to RefSeq transcript variants 2 and 3, respectively. [provided by RefSeq, Nov 2017]

MANE transcript

NM_004176.5

Inheritance

ClinVar variants

P:6U:180B:37

Top phenotype

Ichthyosis follicularis, atrichia, and photophobia syndrome 2; Mucoepithelial dysplasia, hereditary

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr17:17,810,399-17,837,002

External References & Databases

Ensembl (ENSG00000072310)

Transcript & Mutation Effects

hg38 • Region Span ~26.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

IFAP syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100221

Submitter: PanelApp Australia

IFAP syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100221

Submitter: Ambry Genetics

hereditary mucoepithelial dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008017

Submitter: PanelApp Australia

IFAP syndrome 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100221

Submitter: G2P

IFAP syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100221

Submitter: Labcorp Genetics (formerly Invitae)

Hirschsprung diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018309

Submitter: Orphanet

hereditary mucoepithelial dysplasiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008017

Submitter: G2P

Clinical Genomic Database (CGD)

Ichthyosis follicularis, atrichia, and photophobia syndrome 2; Mucoepithelial dysplasia, hereditaryAD

Manifestation: Dermatologic; Ophthalmologic

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: 31790666; 32497488; 32902915

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SREBF1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 158

not providedTotal: 36

not specifiedTotal: 23

Hereditary mucoepithelial dysplasiaTotal: 13

IFAP syndrome 2Total: 13

SREBF1-related disorderTotal: 5

IFAP syndrome 1, with or without BRESHECK syndromeTotal: 3

ObesityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004176.5. 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			4 clinvar	12 clinvar	2 clinvar	18
missense	2 clinvar	1 clinvar	173 clinvar	17 clinvar	6 clinvar	199
nonsense		1 clinvar				1
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	2	4	180	29	8	223

Highest pathogenic variant AF is 0.0000025524757

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004176.5	RefSeq	NP_004167.3	19	MANE Select
ENST00000261646.11	Ensembl	ENSP00000261646.5	19	MANE Select
NM_001005291.3	RefSeq	NP_001005291.1	20	Standard
NM_001321096.3	RefSeq	NP_001308025.1	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
srebf1	Danio rerio	Structure: pancreatic B cell Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

srebf1

Danio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin resistance - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Insulin signaling pathway - Homo sapiens (human)
Metformin Pathway, Pharmacodynamic

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of heart rate by chemical signal
regulation of transcription by RNA polymerase II
lipid metabolic process
aging

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
chromatin binding

Cellular Component

Golgi membrane
nucleus
nuclear envelope
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355815
Coding exons: 20
Length: 26613
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125746
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.98	548	695	0.789	0.0000454	7364
Missense (PolyPhen)		165	249.87	0.66034		2768
Synonymous	1.70	278	317	0.878	0.0000208	2620
Loss of Function	4.40	12	43.2	0.278	0.00000215	482

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00014	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator required for lipid homeostasis. Regulates transcription of the LDL receptor gene as well as the fatty acid and to a lesser degree the cholesterol synthesis pathway (By similarity). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3'). {ECO:0000250|UniProtKB:Q9WTN3}.;

Recessive Scores

pRec: 0.800

Intolerance Scores

LoFtool: 0.388
RVIS EVS: -0.79
RVIS percentile EVS: 12.6

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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