IRF2BPL

protein-coding

interferon regulatory factor 2 binding protein like

Gene summary

This gene encodes a transcription factor that may play a role in regulating female reproductive function. [provided by RefSeq, Jun 2012]

Previous symbols:

C14orf4

MANE transcript

NM_024496.4

Inheritance

ClinVar variants

P:122U:346B:179

Top phenotype

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr14:77,024,543-77,028,708

External References & Databases

Ensembl (ENSG00000119669)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060759

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060759

Submitter: Ambry Genetics

neurodegenerative diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005559

Submitter: ClinGen

Monoallelic variants in *IRF2BPL* were first reported in patients with phenotypes including epilepsy, loss of speech and motor skills, progressive dysphagia, and motor features including dystonia and spasticity in 2018 (Marcogliese et al., PMID: 30057031). Patients may present with some or all of these features beginning at 3-4 months of age, or as late as the fifth decade of life. In the literature, assertions have been made for a relationship between *IRF2BPL* and at least three different autosomal dominant entities: progressive myoclonus epilepsy; developmental and epileptic encephalopathy; and neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in phenotypic variability, mode of inheritance, and variant type. Therefore, we are lumping these three entities into one, autosomal dominant neurodegenerative disease (MONDO:0005559). Twenty-one variants (nonsense and frameshift) that have been reported in 27 probands in 11 publications are included in this curation (PMIDs: 36810721, 30057031, 31621620, 30166628, 37114479, 31583567, 37346291, 34864472, 36127562, 31432588, 32427350). Of note, the majority of reported variants have been de novo; parental testing was unavailable for the remaining individuals. In summary, there is definitive evidence supporting the relationship between *IRF2BPL* and autosomal dominant neurodegenerative disease. This 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 Epilepsy GCEP on the meeting date September 5, 2023 (SOP Version 9).

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060759

Submitter: G2P

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060759

Submitter: PanelApp Australia

neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060759

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresAD

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

Refs: 30057031

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRF2BPL variants in ClinVar

18 Conditions Cataloged

not providedTotal: 343

Inborn genetic diseasesTotal: 150

not specifiedTotal: 147

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresTotal: 136

IRF2BPL-related disorderTotal: 89

See casesTotal: 4

Intellectual disabilityTotal: 3

NeurodegenerationTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024496.4. 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				139 clinvar	2 clinvar	141
missense	3 clinvar	13 clinvar	330 clinvar	34 clinvar		380
nonsense	9 clinvar	24 clinvar	5 clinvar			38
start loss						0
frameshift	30 clinvar	43 clinvar	11 clinvar	3 clinvar	1 clinvar	88
splice donor/acceptor (+/-2bp)						0
Total	42	80	346	176	3	647

Highest pathogenic variant AF is 0.0000039411043

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024496.4	RefSeq	NP_078772.1	1	MANE Select
ENST00000238647.5	Ensembl	ENSP00000238647.3	1	MANE Select

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 transcription by RNA polymerase II
development of secondary female sexual characteristics

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription activator activity, RNA polymerase II-specific
molecular_function
metal ion binding

Cellular Component

extracellular space
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000238647
Coding exons: 1
Length: 4147
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	0.734	377	419	0.899	0.0000220	4934
Missense (PolyPhen)		29	34.784	0.83372		362
Synonymous	-9.69	372	198	1.88	0.0000116	1728
Loss of Function	3.42	3	19.1	0.157	8.70e-7	216

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

Function: FUNCTION: May contribute to the control of female reproductive function (By similarity). May play a role in gene transcription by transactivating GNRH1 promoter and repressing PENK promoter. {ECO:0000250}.;

Recessive Scores

pRec: 0.112

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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