RFX7

protein-coding

regulatory factor X7, the group of Regulatory factor X family

Gene summary

RFX7 is a member of the regulatory factor X (RFX) family of transcription factors (see RFX1, MIM 600006) (Aftab et al., 2008 [PubMed 18673564]).[supplied by OMIM, Mar 2009]

Previous symbols:

RFXDC2

MANE transcript

NM_022841.7

Inheritance

ClinVar variants

P:21U:273B:79

Top phenotype

Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr15:56,087,280-56,245,082

External References & Databases

Ensembl (ENSG00000181827)

Transcript & Mutation Effects

hg38 • Region Span ~157.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957228

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Although a *de novo* protein truncating variant in *RFX7* was reported in an individual with autism spectrum disorder (ASD) as early as 2014 (PMID: 25363760), the first report focusing on variants in *RFX7* in relation to autosomal dominant complex neurodevelopmental disorder was published in 2021 (Harris et al., PMID: 33658631). *RFX7* encodes a member of the regulatory factor X (RFX) family of genes that act as master regulators of central nervous system development and ciliogenesis. Seven unique *de* *novo* variants (3 nonsense, 4 frameshift) reported in 7 probands in 2 publications (PMIDs: 25363760, 33658631) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. All reported variants are *de* *novo*, and the mechanism of disease is suggested to be haploinsufficiency (PMID: 33658631). *RFX7* is highly constrained for loss-of-function variants (pLI = 1), but not missense variants (Z = 2.02, gnomAD v4.1.0). There are a limited number of probands with detailed phenotypic features reported. Of those cases, affected individuals present with motor and speech delays, and intellectual disability; other variable features include ASD, attention deficit hyperactivity disorder, behavioral abnormalities, dysmorphic features, micro/macrocephaly, and sensory hypersensitivity (PMID: 33658631). This gene-disease relationship is also supported by experimental evidence demonstrating that individuals with variants in other RFX genes (*RFX3* and *RFX4*) have been reported with global developmental delay, intellectual disability and ASD (PMID: 33658631). In summary, there is definitive evidence supporting the relationship between *RFX7* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 15, 2024 (SOP Version 11).

intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957228

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0957228

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 33658631; 36334883

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFX7 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 184

not providedTotal: 155

Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalitiesTotal: 37

not specifiedTotal: 19

RFX7-related disorderTotal: 19

Neurodevelopmental disorderTotal: 1

MicrocephalyTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022841.7. 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			2 clinvar	16 clinvar	2 clinvar	20
missense	1 clinvar	3 clinvar	254 clinvar	59 clinvar	2 clinvar	319
nonsense	2 clinvar	3 clinvar	5 clinvar			10
start loss						0
frameshift	2 clinvar	10 clinvar	11 clinvar			23
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	16	273	75	4	373

Highest pathogenic variant AF is 0.0000012393017

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022841.7	RefSeq	NP_073752.6	9	MANE Select
ENST00000559447.8	Ensembl	ENSP00000453281.3	9	MANE Select
NM_001368073.2	RefSeq	NP_001355002.1	6	Standard
NM_001368074.1	RefSeq	NP_001355003.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000423270
Coding exons: 9
Length: 156006
Individuals with no LoFs: 124622
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 124629
p: 0.0000281

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.60	637	761	0.837	0.0000388	9587
Missense (PolyPhen)		201	328.1	0.61262		4112
Synonymous	-0.252	280	275	1.02	0.0000143	2908
Loss of Function	6.13	2	47.6	0.0420	0.00000234	601

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	0.00019	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.103

Essentials

Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.488

Gene Damage Prediction

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