RNF125

protein-coding

ring finger protein 125, the group of Ring finger proteins

Gene summary

This gene encodes a novel E3 ubiquitin ligase that contains a RING finger domain in the N-terminus and three zinc-binding and one ubiquitin-interacting motif in the C-terminus. As a result of myristoylation, this protein associates with membranes and is primarily localized to intracellular membrane systems. The encoded protein may function as a positive regulator in the T-cell receptor signaling pathway. [provided by RefSeq, Mar 2012]

MANE transcript

NM_017831.4

Inheritance

ClinVar variants

P:3U:54B:26

Top phenotype

Tenorio syndrome

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr18:32,018,825-32,088,144

External References & Databases

Ensembl (ENSG00000101695)

Transcript & Mutation Effects

hg38 • Region Span ~69.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tenorio syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014553

Submitter: G2P

Tenorio syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014553

Submitter: Labcorp Genetics (formerly Invitae)

Tenorio syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014553

Submitter: Ambry Genetics

Tenorio syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014553

Submitter: Genomics England PanelApp

Tenorio syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014553

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Tenorio syndromeAD

Manifestation: Allergy/Immunology/Infectious; Musculoskeletal; Neurologic

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

Refs: 25196541

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF125 variants in ClinVar

6 Conditions Cataloged

Tenorio syndromeTotal: 54

Inborn genetic diseasesTotal: 25

not providedTotal: 18

not specifiedTotal: 13

RNF125-related disorderTotal: 10

Hypertrophic cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017831.4. 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				13 clinvar	3 clinvar	16
missense	1 clinvar	2 clinvar	48 clinvar	8 clinvar	2 clinvar	61
nonsense						0
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	2	54	21	5	83

Highest pathogenic variant AF is 0.000008067389

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017831.4	RefSeq	NP_060301.2	6	MANE Select
ENST00000217740.4	Ensembl	ENSP00000217740.3	6	MANE Select
NM_001436860.1	RefSeq	NP_001423789.1	6	Standard
NM_001436861.1	RefSeq	NP_001423790.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RIG-I-like receptor signaling pathway - Homo sapiens (human)
RIG-I-like Receptor Signaling

Biological Process

protein polyubiquitination
adaptive immune response
ubiquitin-dependent protein catabolic process
negative regulation of type I interferon production
negative regulation of RIG-I signaling pathway

Molecular Function

p53 binding
protein binding
zinc ion binding
ubiquitin conjugating enzyme binding
ubiquitin protein ligase activity

Cellular Component

Golgi membrane
VCP-NPL4-UFD1 AAA ATPase complex
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217740
Coding exons: 6
Length: 54842
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.783	109	135	0.810	0.00000713	1506
Missense (PolyPhen)		30	39.584	0.75788		479
Synonymous	0.354	46	49.2	0.936	0.00000238	438
Loss of Function	0.893	8	11.2	0.713	5.56e-7	145

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as DDX58/RIG-I, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53 (PubMed:15843525, PubMed:17460044, PubMed:17643463, PubMed:26027934, PubMed:26471729, PubMed:25591766, PubMed:27411375). Acts as a negative regulator of type I interferon production by mediating ubiquitination of DDX58/RIG-I at 'Lys-181', leading to DDX58/RIG-I degradation (PubMed:17460044, PubMed:26471729). Mediates ubiquitination and subsequent degradation of p53/TP53 (PubMed:25591766). Mediates ubiquitination and subsequent degradation of JAK1 (PubMed:26027934). Acts as a positive regulator of T-cell activation (PubMed:15843525). {ECO:0000269|PubMed:15843525, ECO:0000269|PubMed:17460044, ECO:0000269|PubMed:17643463, ECO:0000269|PubMed:25591766, ECO:0000269|PubMed:26027934, ECO:0000269|PubMed:26471729, ECO:0000269|PubMed:27411375}.;
Disease: DISEASE: Tenorio syndrome (TNORS) [MIM:616260]: A disease characterized by overgrowth, macrocephaly, and intellectual disability. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome. {ECO:0000269|PubMed:25196541}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.309
RVIS EVS: 0.55
RVIS percentile EVS: 81.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.449

Gene Damage Prediction

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