RIF1

protein-coding

replication timing regulatory factor 1, the group of Armadillo like helical domain containing

Gene summary

This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

MANE transcript

NM_018151.5

Inheritance

—

ClinVar variants

U:352B:40

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:151,409,883-151,508,013

External References & Databases

Ensembl (ENSG00000080345)

Transcript & Mutation Effects

hg38 • Region Span ~98.1 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 RIF1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 355

not providedTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018151.5. 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			8 clinvar	6 clinvar	2 clinvar	16
missense			335 clinvar	32 clinvar		367
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	352	38	2	392

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018151.5	RefSeq	NP_060621.3	35	MANE Select
ENST00000444746.7	Ensembl	ENSP00000390181.2	35	MANE Select
NM_001177663.2	RefSeq	NP_001171134.1	34	Standard
NM_001177664.2	RefSeq	NP_001171135.1	34	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
ATM Signaling Network in Development and Disease
DNA Repair
Nonhomologous End-Joining (NHEJ)
DNA Double-Strand Break Repair

Biological Process

negative regulation of transcription by RNA polymerase II
telomere maintenance
double-strand break repair via nonhomologous end joining
chromatin silencing at telomere
cellular response to DNA damage stimulus

Molecular Function

protein binding

Cellular Component

chromosome, telomeric region
nuclear chromatin
condensed chromosome
female pronucleus
male pronucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000243326
Coding exons: 35
Length: 98131
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125741
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.414	1270	1.23e+3	1.03	0.0000606	16238
Missense (PolyPhen)		242	333.04	0.72665		4396
Synonymous	-2.66	503	433	1.16	0.0000217	4659
Loss of Function	8.96	6	105	0.0571	0.00000515	1497

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000061	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.000044	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)- mediated repair of DSBs (PubMed:15342490, PubMed:28241136). In response to DNA damage, interacts with ATM-phosphorylated TP53BP1 (PubMed:23333306, PubMed:28241136). Interaction with TP53BP1 leads to dissociate the interaction between NUDT16L1/TIRR and TP53BP1, thereby unmasking the tandem Tudor-like domain of TP53BP1 and allowing recruitment to DNA DSBs (PubMed:28241136). Once recruited to DSBs, RIF1 and TP53BP1 act by promoting NHEJ-mediated repair of DSBs (PubMed:23333306). In the same time, RIF1 and TP53BP1 specifically counteract the function of BRCA1 by blocking DSBs resection via homologous recombination (HR) during G1 phase (PubMed:23333306). Also required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs (By similarity). Promotes NHEJ of dysfunctional telomeres (By similarity). {ECO:0000250|UniProtKB:Q6PR54, ECO:0000269|PubMed:15342490, ECO:0000269|PubMed:23333306, ECO:0000269|PubMed:28241136}.;

Recessive Scores

pRec: 0.0948

Intolerance Scores

LoFtool: 0.489
RVIS EVS: -1.81
RVIS percentile EVS: 2.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.929

Gene Damage Prediction

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