MYRF

protein-coding

myelin regulatory factor

Gene summary

This gene encodes a transcription factor that is required for central nervous system myelination and may regulate oligodendrocyte differentiation. It is thought to act by increasing the expression of genes that effect myelin production but may also directly promote myelin gene expression. Loss of a similar gene in mouse models results in severe demyelination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

Previous symbols:

C11orf9

MANE transcript

NM_001127392.3

Inheritance

ClinVar variants

P:70U:193B:47

Top phenotype

Encephalitis/encephalopathy, mild, with reversible myelin vacuolization; Cardiac-urogenital syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr11:61,752,636-61,788,518

External References & Databases

Ensembl (ENSG00000124920)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiac-urogenital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032653

Submitter: Labcorp Genetics (formerly Invitae)

cardiac-urogenital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032653

Submitter: G2P

encephalitis/encephalopathy, mild, with reversible myelin vacuolizationLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020853

Submitter: Ambry Genetics

cardiac-urogenital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032653

Submitter: PanelApp Australia

encephalitis/encephalopathy, mild, with reversible myelin vacuolizationLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0020853

Submitter: Labcorp Genetics (formerly Invitae)

cardiac-urogenital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032653

Submitter: Ambry Genetics

hyperopiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0004891

Submitter: G2P

cardiac-urogenital syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032653

Submitter: ClinGen

The *MYRF* gene is located on chromosome 11 at 11q12.2 and encodes the Myelin Regulatory Factor, a transcription factor. *MYRF* was first reported in association with Cardiac-urogenital syndrome (CUGS) in 2018 (Pinz et al., PMID: 29446546). CUGS is characterized postnatally by congenital diaphragmatic hernia, primary pulmonary hypoplasia, congenital heart defects, anomalies of the internal and external genitalia, ocular anomalies, developmental delay, and intellectual disability. Prenatal presentations include hypoplastic left heart syndrome, disorders of sex development in 46,XY fetuses, congenital diaphragmatic hernia, and pulmonary hypoplasia (PMID: 39542847). Nanophthalmos and high hyperopia are common features within the CUGS phenotypic spectrum (PMID: 36375006). Per the ClinGen Lumping and Splitting guidelines, no differences were identified in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, Cardiac-urogenital syndrome (CUGS; MIM: 618280) and Nanophthalmos 1 (MIM: 600165) have been lumped into a single disease entity. The autosomal dominant Encephalitis/encephalopathy, mild, with reversible myelin vacuolization (MIM: 618113) phenotype has been curated separately. At least 59 pathogenic or likely pathogenic variants, including frameshift, nonsense, missense, and splice-altering variants, have been reported in more than 60 affected individuals across 13 publications (PMIDs: 30070761, 29446546, 30532227, 31048900, 31266062, 30985895, 31069960, 31700225, 31172260, 35432193, 35365939, 39542847, 39868768). Six de novo variants are included in this curation. Additional genetic evidence exists in the literature; however, the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be domain-specific. Variants affecting the intramolecular chaperone auto-processing domain result in loss of function, variants within the DNA-binding domain exert a dominant-negative effect, and C-terminal truncating variants have an unclear mechanism but are likely hypomorphic (PMIDs: 31964908, 28160598). This gene–disease relationship is further supported by experimental evidence, including animal models (mouse, zebrafish, and C. elegans), expression analyses, and in vivo and in vitro functional studies (PMIDs: 31048900, 38901241, 33646289, 36129575, 40313921, 33798553, 37584388, 31964908, 36013096, 22956843, 28441531, 28160598, 33950834, 38488284). In summary, there is definitive evidence supporting the relationship between *MYRF* and autosomal dominant Cardiac-urogenital syndrome. This relationship has been consistently demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on July 2, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Encephalitis/encephalopathy, mild, with reversible myelin vacuolization; Cardiac-urogenital syndromeAD

Manifestation: Cardiovascular; Gastrointestinal; Genitourinary; Neurologic; Pulmonary

Intervention: Cardiovascular; Neurologic

Rationale: Encephalitis/encephalopathy, which involves acute reversible encephalopathy in children, and is frequently associated with a trigger, such as a febrile illness, has been reported as being treatable with steroids; Cardiac-urogenital syndrome may involve congenital anomalies (eg, cardiac anomalies), which may benefit from early diagnosis and intervention

Refs: 29265453; 29446546; 30070761; 30532227

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYRF variants in ClinVar

18 Conditions Cataloged

Inborn genetic diseasesTotal: 137

not providedTotal: 73

Cardiac-urogenital syndromeTotal: 56

MYRF-related disorderTotal: 56

Encephalitis/encephalopathy, mild, with reversible myelin vacuolizationTotal: 17

not specifiedTotal: 14

Abnormal heart morphologyTotal: 9

Urogenital tract malformationTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127392.3. 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			4 clinvar	19 clinvar	6 clinvar	29
missense	4 clinvar	16 clinvar	181 clinvar	16 clinvar	4 clinvar	221
nonsense	10 clinvar	5 clinvar	1 clinvar			16
start loss						0
frameshift	15 clinvar	14 clinvar	1 clinvar			30
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	6 clinvar	2 clinvar		14
Total	31	39	193	37	10	310

Highest pathogenic variant AF is 0.00002172863

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127392.3	RefSeq	NP_001120864.1	27	MANE Select
ENST00000278836.10	Ensembl	ENSP00000278836.4	27	MANE Select
NM_013279.4	RefSeq	NP_037411.1	26	Standard
ENST00000265460.10	Ensembl	ENSP00000265460.5	26	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
proteolysis
oligodendrocyte development
central nervous system myelination
positive regulation of myelination

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
peptidase activity
sequence-specific DNA binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
endoplasmic reticulum membrane
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000278836
Coding exons: 27
Length: 35877
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125729
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.29	456	701	0.650	0.0000428	7418
Missense (PolyPhen)		168	300.68	0.55874		3146
Synonymous	1.16	270	295	0.914	0.0000196	2345
Loss of Function	6.55	2	53.9	0.0371	0.00000264	595

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Myelin regulatory factor: Constitutes a precursor of the transcription factor. Mediates the autocatalytic cleavage that releases the Myelin regulatory factor, N-terminal component that specifically activates transcription of central nervous system (CNS) myelin genes (PubMed:23966832). {ECO:0000269|PubMed:23966832}.; FUNCTION: Myelin regulatory factor, N-terminal: Transcription factor that specifically activates expression of myelin genes such as MBP, MOG, MAG, DUSP15 and PLP1 during oligodendrocyte (OL) maturation, thereby playing a central role in oligodendrocyte maturation and CNS myelination. Specifically recognizes and binds DNA sequence 5'-CTGGYAC-3' in the regulatory regions of myelin- specific genes and directly activates their expression. Not only required during oligodendrocyte differentiation but is also required on an ongoing basis for the maintenance of expression of myelin genes and for the maintenance of a mature, viable oligodendrocyte phenotype (PubMed:23966832). {ECO:0000269|PubMed:23966832}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: -1.08
RVIS percentile EVS: 7.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N

Gene Damage Prediction

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