ATRIP

protein-coding

ATR interacting protein, the group of Armadillo like helical domain containing

Gene summary

This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

MANE transcript

NM_130384.3

Inheritance

AR, AD

ClinVar variants

P:1U:876B:433

Top phenotype

Seckel syndrome

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr3:48,446,710-48,467,645

External References & Databases

Ensembl (ENSG00000164053)

Transcript & Mutation Effects

hg38 • Region Span ~20.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Seckel syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: PanelApp Australia

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

breast cancerMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: G2P

hereditary breast carcinomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

*ATRIP* was first reported concerning autosomal dominant inheritance and breast cancer susceptibility in 2023 (Cybulski C, et al., PMID: 36977412). Breast cancer (referring to mammary carcinoma) is histopathological and almost certainly etiologically and genetically heterogeneous. Familial occurrence has indicated important genetic factors (OMIM 114480). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. One variant (*ATRIP*:c.1152_1155del) reported in breast cancer patients in one publication (PMID: 36977412) is included in this curation. More evidence is available in the literature (Wilcox N, et al., PMID: 37592023), reported associations between protein-truncating variants in *ATRIP* and breast cancer (P < 1 × 10−4.). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence from in vitro functional assays (PMID: 36977412). Immunohistochemistry and functional studies showed the *ATRIP* c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. In summary, limited evidence supports the relationship between *ATRIP* and autosomal dominant inheritance Breast cancer susceptibility. This relationship has been demonstrated in patients with monoallelic mutations in *ATRIP* (PMIDs: 36977412, 37592023). The ClinGen Hereditary Cancer GCEP approved this classification on the meeting date of May 24, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATRIP variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 1285

not providedTotal: 286

ATRIP-related disorderTotal: 7

Microcephalic Primordial Dwarfism with immunodeficiencyTotal: 2

Seckel syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130384.3. 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			16 clinvar	354 clinvar	2 clinvar	372
missense			809 clinvar	75 clinvar	2 clinvar	886
nonsense			17 clinvar			17
start loss			1 clinvar			1
frameshift			20 clinvar			20
splice donor/acceptor (+/-2bp)		1 clinvar	13 clinvar			14
Total	0	1	876	429	4	1310

Highest pathogenic variant AF is 0.0000032575879

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_130384.3	RefSeq	NP_569055.1	13	MANE Select
ENST00000320211.10	Ensembl	ENSP00000323099.3	13	MANE Select
NM_001271022.2	RefSeq	NP_001257951.1	11	Standard
NM_001271023.2	RefSeq	NP_001257952.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
miRNA Regulation of DNA Damage Response
DNA Damage Response
HDR through Single Strand Annealing (SSA)
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)

Biological Process

DNA damage checkpoint
DNA replication
interstrand cross-link repair

Molecular Function

protein binding
K63-linked polyubiquitin modification-dependent protein binding

Cellular Component

nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320211
Coding exons: 13
Length: 19002
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	361	422	0.856	0.0000217	5093
Missense (PolyPhen)		108	133.98	0.80607		1725
Synonymous	1.09	164	183	0.897	0.0000101	1655
Loss of Function	3.22	14	34.3	0.408	0.00000173	400

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00017	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein. {ECO:0000269|PubMed:12791985}.;

Recessive Scores

pRec: 0.205

Intolerance Scores

LoFtool: 0.793
RVIS EVS: -0.75
RVIS percentile EVS: 13.74

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.460

Gene Damage Prediction

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