PRR12

protein-coding

proline rich 12

Gene summary

This gene encodes a proline-rich protein that contains two A-T hook DNA binding domains. A chromosomal translocation and gene fusion between this gene and zinc finger, MIZ-type containing 1 (Gene ID: 57178) may underlie intellectual disability and neuropsychiatric problems in a human patient. Enriched expression of this gene in embryonic mouse brain suggests that this gene may play a role in nervous system development. [provided by RefSeq, Jul 2016]

Previous symbols:

KIAA1205

MANE transcript

NM_020719.3

Inheritance

ClinVar variants

P:88U:461B:272

Top phenotype

Neuroocular syndrome 1

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:49,591,182-49,626,439

External References & Databases

Ensembl (ENSG00000126464)

Transcript & Mutation Effects

hg38 • Region Span ~35.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuroocular syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0971007

Submitter: G2P

neuroocular syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859193

Submitter: Labcorp Genetics (formerly Invitae)

neuroocular syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0971007

Submitter: PanelApp Australia

neuroocular syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859193

Submitter: ClinGen

The PRR12 gene is located on chromosome 19 at 19q13.33 and encodes the protein proline rich 12. PRR12 was first reported in relation to autosomal dominant neuroocular syndrome in 2018 (Leduc et al., PMID: 29556724). This gene-disease relationship is supported by strong case-level evidencea but no experimental evidence has been scored. Seven variants (2 frameshift, 2 nonsense, 2 essential splice sites (one inherited from an affected parent), and 1 missense) that have beene reported in seven probands from three publications are included in this curation (PMIDs: 29556724, 33824499, 33314030). More evidence is available in the literature (over 28 additional cases, mostly protein truncating variants but occasional missense without functional evidence have been reported), but the maximum score for genetic evidence (12 pts.) has been reached. Haploinsufficiency/loss of function is the suggested mechanism of disease. The function of the PRR12 protein has not been well characterized, and little supporting experimental evidence is available. PRR12 has been suggested to physically interact with SOX2 (PMID: 28794006), which is associated with a clinical phenotype with overlapping features, syndromic microphthalmia. Predicted reduced PRR12 expression has also been associated with acquired ocular and renal clinical phenotypes in human biobank data (PMID: 33824499). However, the SD-GCEP did not think these data were strong enough to score within the framework for this monogenic gene-disease relationship. In summary, PRR12 is definitively associated with autosomal dominant neuroocular syndrome. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 01/19/2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Neuroocular syndrome 1AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Renal

Rationale: The condition can include congenital anomalies such as cardiac and renal anomalies, and awareness may allow early interventions (eg, surgical repair of cardiac anomalies)

Refs: 29556724; 33314030; 33824499

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRR12 variants in ClinVar

19 Conditions Cataloged

Inborn genetic diseasesTotal: 385

not providedTotal: 302

PRR12-related disorderTotal: 107

not specifiedTotal: 94

Neuroocular syndrome 1Total: 45

Neuroocular syndromeTotal: 27

complex microphthalmiaTotal: 4

Motor delayTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020719.3. 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			7 clinvar	139 clinvar	21 clinvar	167
missense		3 clinvar	447 clinvar	110 clinvar	2 clinvar	562
nonsense	12 clinvar	9 clinvar	5 clinvar			26
start loss						0
frameshift	35 clinvar	27 clinvar	1 clinvar			63
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	1 clinvar			3
Total	48	40	461	249	23	821

Highest pathogenic variant AF is 0.000009787021

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_020719.3	RefSeq	NP_065770.1	14	MANE Select
ENST00000418929.7	Ensembl	ENSP00000394510.1	14	MANE Select
ENST00001138234.1	Ensembl	ENSP00000812664.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

nucleus
postsynaptic density
cell junction
neuron projection
postsynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418929
Coding exons: 14
Length: 34797
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	2.98	970	1.27e+3	0.765	0.0000859	12597
Missense (PolyPhen)		120	201.01	0.597		1845
Synonymous	-3.29	689	588	1.17	0.0000443	4644
Loss of Function	7.04	0	57.7	0.00	0.00000284	700

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

Recessive Scores

pRec: 0.114

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.186

Gene Damage Prediction

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