RAD1

protein-coding

RAD1 checkpoint DNA exonuclease, the group of Checkpoint clamp complex

Gene summary

This gene encodes a component of a heterotrimeric cell cycle checkpoint complex, known as the 9-1-1 complex, that is activated to stop cell cycle progression in response to DNA damage or incomplete DNA replication. The 9-1-1 complex is recruited by RAD17 to affected sites where it may attract specialized DNA polymerases and other DNA repair effectors. Alternatively spliced transcript variants of this gene have been described. [provided by RefSeq, Jan 2009]

MANE transcript

NM_002853.4

Inheritance

—

ClinVar variants

U:45B:7

Top phenotype

RAD1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr5:34,905,260-34,918,989

External References & Databases

Ensembl (ENSG00000113456)

Transcript & Mutation Effects

hg38 • Region Span ~13.7 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 RAD1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 37

RAD1-related disorderTotal: 16

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002853.4. 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			2 clinvar	4 clinvar		6
missense			40 clinvar	1 clinvar	2 clinvar	43
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	45	5	2	52

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002853.4	RefSeq	NP_002844.1	5	MANE Select
ENST00000382038.7	Ensembl	ENSP00000371469.2	5	MANE Select
ENST00000325577.8	Ensembl	ENSP00000313467.4	2	Standard
ENST00000341754.8	Ensembl	ENSP00000340879.4	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cellular senescence - Homo sapiens (human)
miRNA Regulation of DNA Damage Response
ATR Signaling
DNA Damage Response
HDR through Single Strand Annealing (SSA)

Biological Process

DNA damage checkpoint
DNA repair
cellular response to DNA damage stimulus
substantia nigra development
meiotic recombination checkpoint

Molecular Function

damaged DNA binding
protein binding
3'-5' exonuclease activity
exodeoxyribonuclease III activity

Cellular Component

nucleus
nucleoplasm
chromosome
checkpoint clamp complex
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382038
Coding exons: 5
Length: 13726
Individuals with no LoFs: 125599
Homozygous LoFs: 0
Heterozygous LoFs: 149
Defined: 125748
p: 0.000593

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.270	136	145	0.937	0.00000674	1854
Missense (PolyPhen)		38	48.922	0.77675		651
Synonymous	1.05	42	51.6	0.814	0.00000232	527
Loss of Function	1.32	8	13.2	0.607	6.89e-7	158

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00018	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00020	0.00020	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair (PubMed:10846170, PubMed:10884395). The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex (PubMed:12578958). Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER) (PubMed:15871698). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates (PubMed:15314187, PubMed:15556996, PubMed:15871698). The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase (PubMed:21659603). Isoform 1 possesses 3'->5' double stranded DNA exonuclease activity (PubMed:9660799). {ECO:0000269|PubMed:10846170, ECO:0000269|PubMed:10884395, ECO:0000269|PubMed:12578958, ECO:0000269|PubMed:15314187, ECO:0000269|PubMed:15556996, ECO:0000269|PubMed:15871698, ECO:0000269|PubMed:21659603, ECO:0000269|PubMed:9660799}.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.844
RVIS EVS: 0.19
RVIS percentile EVS: 67.03

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.984

Gene Damage Prediction

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