PRRX1

protein-coding

paired related homeobox 1, the group of PRD class homeoboxes and pseudogenes

Gene summary

The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription co-activator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns. [provided by RefSeq, Jul 2008]

Previous symbols:

PMX1

MANE transcript

NM_022716.4

Inheritance

AD, AR

ClinVar variants

P:6U:30B:11

Top phenotype

Agnathia-otocephaly complex

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr1:170,662,728-170,739,421

External References & Databases

Ensembl (ENSG00000116132)

Transcript & Mutation Effects

hg38 • Region Span ~76.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

agnathia-otocephaly complexLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008740

Submitter: G2P

agnathia-otocephaly complexLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008740

Submitter: Labcorp Genetics (formerly Invitae)

agnathia-otocephaly complexLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008740

Submitter: G2P

agnathia-otocephaly complexSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008740

Submitter: PanelApp Australia

agnathia-otocephaly complexSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008740

Submitter: Orphanet

multiple congenital anomalies/dysmorphic syndrome-intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015159

Submitter: Ambry Genetics

agnathia-otocephaly complexLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008740

Submitter: Ambry Genetics

craniosynostosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015469

Submitter: G2P

Clinical Genomic Database (CGD)

Agnathia-otocephaly complexAD/AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial

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: 12244557; 21294718; 22211708; 23444262

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRRX1 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 20

PRRX1-related disorderTotal: 11

Agnathia-otocephaly complexTotal: 10

not providedTotal: 6

not specifiedTotal: 4

Craniosynostosis syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022716.4. 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				6 clinvar		6
missense	2 clinvar	1 clinvar	29 clinvar	4 clinvar	1 clinvar	37
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar					2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	1	30	10	1	47

Highest pathogenic variant AF is 0.0000013681406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022716.4	RefSeq	NP_073207.1	4	MANE Select
ENST00000239461.11	Ensembl	ENSP00000239461.6	4	MANE Select
NM_006902.5	RefSeq	NP_008833.1	4	Standard
ENST00000367760.7	Ensembl	ENSP00000356734.3	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
prrx1a	Danio rerio	Structure: atrium Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

prrx1a

Danio rerio

Structure: atrium

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of mesenchymal cell proliferation
embryonic limb morphogenesis
inner ear morphogenesis
middle ear morphogenesis

Molecular Function

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
transcription coactivator activity
HMG box domain binding

Cellular Component

nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000239461
Coding exons: 4
Length: 76692
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.02	114	149	0.764	0.00000845	1581
Missense (PolyPhen)		54	72.41	0.74575		768
Synonymous	-1.61	79	62.7	1.26	0.00000358	498
Loss of Function	2.37	3	11.8	0.255	7.53e-7	114

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional regulator of muscle creatine kinase (MCK) and so has a role in the establishment of diverse mesodermal muscle types. The protein binds to an A/T-rich element in the muscle creatine enhancer (By similarity). {ECO:0000250}.;
Disease: DISEASE: Agnathia-otocephaly complex (AGOTC) [MIM:202650]: A rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal. {ECO:0000269|PubMed:21294718}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.203

Intolerance Scores

LoFtool: 0.0691
RVIS EVS: 0.28
RVIS percentile EVS: 71.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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