SREBF2

protein-coding

sterol regulatory element binding transcription factor 2, the group of MicroRNA protein coding host genes|Basic helix-loop-helix proteins

Gene summary

This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_004599.4

Inheritance

AD, AR

ClinVar variants

U:191B:24

Top phenotype

SREBF2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr22:41,833,105-41,907,306

External References & Databases

Ensembl (ENSG00000198911)

Transcript & Mutation Effects

hg38 • Region Span ~74.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple congenital anomalies/dysmorphic syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

neurocutaneous syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0042983

Submitter: PanelApp Australia

hereditary spastic paraplegiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SREBF2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 174

SREBF2-related disorderTotal: 19

not providedTotal: 18

HypercholesterolemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004599.4. 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			2 clinvar	9 clinvar	5 clinvar	16
missense			179 clinvar	8 clinvar	2 clinvar	189
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	191	17	7	215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004599.4	RefSeq	NP_004590.2	19	MANE Select
ENST00000361204.9	Ensembl	ENSP00000354476.4	19	MANE Select
ENST00000424354.5	Ensembl	ENSP00000395728.1	11	Standard
ENST00000435061.1	Ensembl	ENSP00000412287.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
srebf2	Danio rerio	Structure: liver Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

srebf2

Danio rerio

Structure: liver

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sterol Regulatory Element-Binding Proteins (SREBP) signalling
SREBF and miR33 in cholesterol and lipid homeostasis
Angiopoietin Like Protein 8 Regulatory Pathway
Metabolism of lipids
Regulation of cholesterol biosynthesis by SREBP (SREBF)

Biological Process

negative regulation of transcription by RNA polymerase II
lipid metabolic process
cholesterol metabolic process
cellular response to starvation
positive regulation of cholesterol storage

Molecular Function

C-8 sterol isomerase activity
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
protein binding

Cellular Component

Golgi membrane
nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361204
Coding exons: 19
Length: 74204
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.679	605	654	0.925	0.0000427	7310
Missense (PolyPhen)		180	225.29	0.79899		2486
Synonymous	-0.178	275	271	1.01	0.0000177	2405
Loss of Function	5.05	12	50.9	0.236	0.00000280	531

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000033	0.000033	rare
Other	0.00036	0.00033	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 cholesterol and to a lesser degree the fatty acid synthesis pathway (By similarity). Binds the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3') found in the flanking region of the LDRL and HMG-CoA synthase genes. {ECO:0000250}.;

Recessive Scores

pRec: 0.474

Intolerance Scores

LoFtool: 0.357
RVIS EVS: -1.83
RVIS percentile EVS: 2.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
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	High
Cancer	Medium	Medium	Medium