RFC4

protein-coding

replication factor C subunit 4, the group of AAA ATPases

Gene summary

The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also named activator 1, is a protein complex consisting of five distinct subunits of 140, 40, 38, 37, and 36 kD. This gene encodes the 37 kD subunit. This subunit forms a core complex with the 36 and 40 kDa subunits. The core complex possesses DNA-dependent ATPase activity, which was found to be stimulated by PCNA in an in vitro system. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002916.5

Inheritance

ClinVar variants

P:6U:67B:4

Top phenotype

Morimoto-Ryu-Malicdan neuromuscular syndrome

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr3:186,789,880-186,807,058

External References & Databases

Ensembl (ENSG00000163918)

Transcript & Mutation Effects

hg38 • Region Span ~17.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Morimoto-Ryu-Malicdan neuromuscular syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0975848

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Morimoto-Ryu-Malicdan neuromuscular syndromeAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Indivdiuals have been described with cardiomyopathy, and awareness may allow prompt diagnosis and management

Refs: 39106866

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFC4 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 63

Morimoto-Ryu-Malicdan neuromuscular syndromeTotal: 14

not providedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002916.5. 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		2
missense		2 clinvar	61 clinvar	2 clinvar		65
nonsense			2 clinvar			2
start loss						0
frameshift	3 clinvar	1 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	3	67	4	0	77

Highest pathogenic variant AF is 0.00046457493

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002916.5	RefSeq	NP_002907.1	10	MANE Select
ENST00000296273.7	Ensembl	ENSP00000296273.2	10	MANE Select
NM_181573.3	RefSeq	NP_853551.1	10	Standard
ENST00000392481.6	Ensembl	ENSP00000376272.2	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rfc4	Danio rerio	Structure: head Quality: pointed abnormal

Gene / Model

Organism

Observed Phenotype

rfc4

Danio rerio

Structure: head

Quality: pointed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
Mismatch repair - Homo sapiens (human)
DNA replication - Homo sapiens (human)
Gastric Cancer Network 2
Retinoblastoma (RB) in Cancer

Biological Process

DNA replication
DNA-dependent DNA replication
DNA strand elongation involved in DNA replication
transcription-coupled nucleotide-excision repair
nucleotide-excision repair, DNA incision, 5'-to lesion

Molecular Function

DNA clamp loader activity
protein binding
ATP binding
enzyme binding
single-stranded DNA-dependent ATPase activity

Cellular Component

nucleus
nucleoplasm
DNA replication factor C complex
Ctf18 RFC-like complex
Elg1 RFC-like complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392481
Coding exons: 10
Length: 17179
Individuals with no LoFs: 125613
Homozygous LoFs: 0
Heterozygous LoFs: 135
Defined: 125748
p: 0.000537

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.288	211	200	1.06	0.0000107	2338
Missense (PolyPhen)		56	78.881	0.70993		915
Synonymous	0.276	68	71.0	0.958	0.00000388	713
Loss of Function	1.94	14	24.3	0.576	0.00000166	258

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00072	0.00072	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00065	0.00065	rare
European (Non-Finnish)	0.00044	0.00044	rare
South Asian	0.00069	0.00069	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit may be involved in the elongation of the multiprimed DNA template.;

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.975
RVIS EVS: -0.67
RVIS percentile EVS: 15.76

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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