PRDM12

protein-coding

PR/SET domain 12, the group of PR/SET domain family|Zinc fingers C2H2-type

Gene summary

This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]

MANE transcript

NM_021619.3

Inheritance

ClinVar variants

P:21U:144B:94

Top phenotype

Neuropathy, hereditary sensory and autonomic, type VIII

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr9:130,664,594-130,682,986

External References & Databases

Ensembl (ENSG00000130711)

Transcript & Mutation Effects

hg38 • Region Span ~18.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital insensitivity to pain-hypohidrosis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014662

Submitter: Orphanet

congenital insensitivity to pain-hypohidrosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014662

Submitter: Labcorp Genetics (formerly Invitae)

congenital insensitivity to pain-hypohidrosis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014662

Submitter: G2P

congenital insensitivity to pain-hypohidrosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014662

Submitter: PanelApp Australia

hereditary sensory and autonomic neuropathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015364

Submitter: Illumina

Clinical Genomic Database (CGD)

Neuropathy, hereditary sensory and autonomic, type VIIIAR

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: Insensitivity to pain can result in injuries and infections

Refs: 26005867

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRDM12 variants in ClinVar

6 Conditions Cataloged

Congenital insensitivity to pain-hypohidrosis syndromeTotal: 252

Inborn genetic diseasesTotal: 86

not providedTotal: 58

PRDM12-related disorderTotal: 24

not specifiedTotal: 21

Hereditary sensory and autonomic neuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021619.3. 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			1 clinvar	84 clinvar		85
missense	5 clinvar	5 clinvar	139 clinvar	5 clinvar		154
nonsense	1 clinvar	1 clinvar	1 clinvar			3
start loss			2 clinvar			2
frameshift	4 clinvar	1 clinvar	1 clinvar	2 clinvar	1 clinvar	9
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar		2 clinvar		6
Total	12	9	144	93	1	259

Highest pathogenic variant AF is 0.00025544708

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021619.3	RefSeq	NP_067632.2	5	MANE Select
ENST00000253008.3	Ensembl	ENSP00000253008.2	5	MANE Select
ENST00000676323.1	Ensembl	ENSP00000502471.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
prdm12b	Danio rerio	Structure: hindbrain interneuron Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

prdm12b

Danio rerio

Structure: hindbrain interneuron

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
sensory perception of pain
neurogenesis
neuron projection development
methylation

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253008
Coding exons: 5
Length: 18388
Individuals with no LoFs: 123773
Homozygous LoFs: 18
Heterozygous LoFs: 1703
Defined: 125494
p: 0.00688

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.67	123	187	0.656	0.00000934	2364
Missense (PolyPhen)		28	61	0.45902		656
Synonymous	-0.287	85	81.7	1.04	0.00000416	740
Loss of Function	3.07	1	12.9	0.0776	5.51e-7	145

Population LoF Frequency

Population	CAF	p-value	Status
African	0.098	0.083	notable
Latino/Admixed American	0.0054	0.0046	notable
Ashkenazi Jewish	0.00050	0.00040	rare
East Asian	0.0026	0.0021	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.0011	0.00085	notable
South Asian	0.0047	0.0037	notable
Other	0.0035	0.0029	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the positive regulation of histone H3-K9 dimethylation. {ECO:0000269|PubMed:26005867}.;
Disease: DISEASE: Neuropathy, hereditary sensory and autonomic, 8 (HSAN8) [MIM:616488]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN8 patients manifest congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Some patients may also have decreased sweating and tear production. {ECO:0000269|PubMed:26005867}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.522

Gene Damage Prediction

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