PRDM8

protein-coding

PR/SET domain 8, the group of PR/SET domain family|Lysine methyltransferases

Gene summary

This gene encodes a protein that belongs to a conserved family of histone methyltransferases that predominantly act as negative regulators of transcription. The encoded protein contains an N-terminal Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domain and a double zinc-finger domain. Knockout of this gene in mouse results in mistargeting by neurons of the dorsal telencephalon, abnormal itch-like behavior, and impaired differentiation of rod bipolar cells. In humans, the protein has been shown to interact with the phosphatase laforin and the ubiquitin ligase malin, which regulate glycogen construction in the cytoplasm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

MANE transcript

NM_001099403.2

Inheritance

ClinVar variants

P:1U:282B:183

Top phenotype

Epilepsy, progressive myoclonic, 10

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr4:80,183,879-80,204,329

External References & Databases

Ensembl (ENSG00000152784)

Transcript & Mutation Effects

hg38 • Region Span ~20.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

early-onset Lafora body diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014717

Submitter: Orphanet

early-onset Lafora body diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014717

Submitter: PanelApp Australia

early-onset Lafora body diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014717

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, progressive myoclonic, 10AR

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

Comments: As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection

Refs: 22961547

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRDM8 variants in ClinVar

4 Conditions Cataloged

Early-onset Lafora body diseaseTotal: 435

not specifiedTotal: 121

not providedTotal: 19

PRDM8-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001099403.2. 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				172 clinvar	7 clinvar	179
missense	1 clinvar		279 clinvar	3 clinvar	1 clinvar	284
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	1	0	282	175	8	466

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001099403.2	RefSeq	NP_001092873.1	3	MANE Select
ENST00000415738.3	Ensembl	ENSP00000406998.2	3	MANE Select
NM_020226.4	RefSeq	NP_064611.3	3	Standard
ENST00000339711.8	Ensembl	ENSP00000339764.4	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
oligodendrocyte development
methylation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
methyltransferase activity
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339711
Coding exons: 3
Length: 20451
Individuals with no LoFs: 124788
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 124794
p: 0.0000240

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0172	331	332	0.997	0.0000159	4368
Missense (PolyPhen)		84	109.25	0.76886		1387
Synonymous	-1.30	168	148	1.14	0.00000751	1478
Loss of Function	3.29	3	18.1	0.166	7.79e-7	227

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	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable histone methyltransferase, preferentially acting on 'Lys-9' of histone H3 (By similarity). Involved in the control of steroidogenesis through transcriptional repression of steroidogenesis marker genes such as CYP17A1 and LHCGR (By similarity). Forms with BHLHE22 a transcriptional repressor complex controlling genes involved in neural development and neuronal differentiation (By similarity). In the retina, it is required for rod bipolar and type 2 OFF-cone bipolar cell survival (By similarity). {ECO:0000250|UniProtKB:Q8BZ97}.;

Recessive Scores

pRec: 0.105

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.139

Gene Damage Prediction

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