RINT1

protein-coding

RAD50 interactor 1, the group of NRZ tethering complex

Gene summary

This gene encodes a protein first identified for its ability to interact with the RAD50 double strand break repair protein, with the resulting interaction implicated in the regulation of cell cycle progression and telomere length. The encoded protein may also play a role in trafficking of cellular cargo from the endosome to the trans-Golgi network. Mutations in this gene may be associated with breast cancer in human patients. [provided by RefSeq, Oct 2016]

MANE transcript

NM_021930.6

Inheritance

AR, AD

ClinVar variants

P:61U:1167B:522

Top phenotype

Infantile liver failure syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr7:105,532,169-105,567,677

External References & Databases

Ensembl (ENSG00000135249)

Transcript & Mutation Effects

hg38 • Region Span ~35.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile liver failure syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032844

Submitter: G2P

infantile liver failure syndrome 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032844

Submitter: Ambry Genetics

familial ovarian cancerNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

infantile liver failure syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032844

Submitter: Labcorp Genetics (formerly Invitae)

breast cancerNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

hereditary spastic paraplegiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: PanelApp Australia

infantile liver failure syndrome 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014659

Submitter: Orphanet

infantile liver failure syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032844

Submitter: PanelApp Australia

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

RINT1 (RAD50 Interactor 1) encodes a protein first identified for its ability to interact with the RAD50 double strand break repair protein, with the resulting interaction implicated in the regulation of cell cycle progression and telomere length. RINT1 also plays a role in trafficking of cellular cargo from the endosome to the trans-Golgi network. Biallelic RINT1 mutations are associated with Infantile liver failure syndrome 3. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we describe curation for hereditary breast cancer (refute the association with breast cancer) in this curation. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of RINT1 in cell cycle regulation. **Summary of Case-Control Data: 0.5 POINTS** This gene-disease relationship has been studied in at least 5 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in RINT1 and breast cancer. Likewise, two more case-control studies with smaller case and control sizes did not find significant association of breast cancer with pathogenic RINT1 variant (PMID:35884425) and missense RINT1 variants (PMID:27544226). However, a case-control study with small population size including 29 missense and 2 in-frame deletion RINT1 variants showed significant associations to breast cancer (0.5 points, PMID: 25050558). **Summary of Experimental Data: 3 POINTS** While major case-control studies did not support the gene-disease association, experimental data reported the physical interaction of RINT1 and RAD50, which further regulate cell cycle (0.5 points, PMID:11096100). Rint1-deficient fibroblasts showed a significant increase in chromosomal aberrations such as sister chromatid fusion (0.5 points, PMID:26383973). Rint-1 heterozygous mice also developed mammary gland adenocarcinoma (2 points, PMID:17470549). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between RINT1 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 9/26/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Infantile liver failure syndrome 3AR

Manifestation: Gastrointestinal; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Liver transplant has been described

Refs: 31204009

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RINT1 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 1606

not providedTotal: 843

Infantile liver failure syndrome 3Total: 39

RINT1-related disorderTotal: 34

Hereditary breast ovarian cancer syndromeTotal: 7

Familial ovarian cancerTotal: 2

Thyroid cancer, nonmedullary, 1Total: 2

Fulminant hepatic failureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021930.6. 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			11 clinvar	457 clinvar	5 clinvar	473
missense	1 clinvar	1 clinvar	1110 clinvar	58 clinvar	2 clinvar	1172
nonsense	8 clinvar	7 clinvar	13 clinvar			28
start loss						0
frameshift	14 clinvar	13 clinvar	22 clinvar			49
splice donor/acceptor (+/-2bp)	2 clinvar	15 clinvar	11 clinvar			28
Total	25	36	1167	515	7	1750

Highest pathogenic variant AF is 0.000019209177

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021930.6	RefSeq	NP_068749.3	15	MANE Select
ENST00000257700.7	Ensembl	ENSP00000257700.2	15	MANE Select
NM_001346599.2	RefSeq	NP_001333528.1	13	Standard
NM_001346600.2	RefSeq	NP_001333529.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
COPI-dependent Golgi-to-ER retrograde traffic
Golgi-to-ER retrograde transport
Intra-Golgi and retrograde Golgi-to-ER traffic

Biological Process

retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
Golgi organization
cell cycle
protein transport
regulation of ER to Golgi vesicle-mediated transport

Molecular Function

protein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
cytosol
Dsl1/NZR complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257700
Coding exons: 15
Length: 35593
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 102
Defined: 125748
p: 0.000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.825	363	410	0.885	0.0000204	5203
Missense (PolyPhen)		81	110.69	0.73174		1499
Synonymous	-0.485	158	150	1.05	0.00000786	1479
Loss of Function	2.49	27	45.1	0.599	0.00000250	507

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00051	0.00049	rare
Latino/Admixed American	0.00027	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00033	0.00033	rare
Other	0.00051	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER. May play a role in cell cycle checkpoint control (PubMed:11096100). Essential for telomere length control (PubMed:16600870). {ECO:0000269|PubMed:11096100, ECO:0000269|PubMed:16600870, ECO:0000305}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.836
RVIS EVS: -0.31
RVIS percentile EVS: 32.15

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.894

Gene Damage Prediction

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