CHFR

protein-coding

checkpoint with forkhead and ring finger domains, the group of Ring finger proteins

Gene summary

This gene encodes an E3 ubiquitin-protein ligase required for the maintenance of the antephase checkpoint that regulates cell cycle entry into mitosis and, therefore, may play a key role in cell cycle progression and tumorigenesis. The encoded protein has an N-terminal forkhead-associated domain, a central RING-finger domain, and a cysteine-rich C-terminal region. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Mar 2014]

MANE transcript

NM_001161346.2

Inheritance

—

ClinVar variants

P:1U:97B:6

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr12:132,822,187-132,956,304

External References & Databases

Ensembl (ENSG00000072609)

Transcript & Mutation Effects

hg38 • Region Span ~134.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHFR variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 92

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001161346.2. 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	1 clinvar	2 clinvar	7
missense			90 clinvar	3 clinvar		93
nonsense		1 clinvar				1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	97	4	2	104

Highest pathogenic variant AF is 7.265393e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 140 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001161346.2	RefSeq	NP_001154818.1	17	MANE Select
ENST00000450056.7	Ensembl	ENSP00000398735.2	17	MANE Select
NM_001161344.1	RefSeq	NP_001154816.1	17	Standard
NM_001161345.1	RefSeq	NP_001154817.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein polyubiquitination
ubiquitin-dependent protein catabolic process
mitotic cell cycle checkpoint
protein ubiquitination
modification-dependent protein catabolic process

Molecular Function

nucleotide binding
ubiquitin-protein transferase activity
protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

nucleus
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000432561
Coding exons: 17
Length: 134118
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125748
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	325	392	0.828	0.0000250	4267
Missense (PolyPhen)		86	126.53	0.67969		1323
Synonymous	0.221	166	170	0.978	0.0000121	1288
Loss of Function	3.64	12	35.4	0.339	0.00000159	436

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress. {ECO:0000269|PubMed:10935642, ECO:0000269|PubMed:11807090, ECO:0000269|PubMed:11912157, ECO:0000269|PubMed:14562038, ECO:0000269|PubMed:14694445, ECO:0000269|PubMed:18172500, ECO:0000269|PubMed:19182791}.;

Recessive Scores

pRec: 0.161

Intolerance Scores

LoFtool: 0.645
RVIS EVS: -0.4
RVIS percentile EVS: 26.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.855

Gene Damage Prediction

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