RNF135

protein-coding

ring finger protein 135, the group of Ring finger proteins

Gene summary

The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene is located in a chromosomal region known to be frequently deleted in patients with neurofibromatosis. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032322.4

Inheritance

ClinVar variants

P:1U:88B:31

Top phenotype

Macrocephaly, macrosomia, facial dysmorphism syndrome

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr17:30,970,984-30,999,911

External References & Databases

Ensembl (ENSG00000181481)

Transcript & Mutation Effects

hg38 • Region Span ~28.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

overgrowth-macrocephaly-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013617

Submitter: Orphanet

overgrowth syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019716

Submitter: Ambry Genetics

overgrowth-macrocephaly-facial dysmorphism syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013617

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Macrocephaly, macrosomia, facial dysmorphism syndromeAD

Manifestation: Craniofacial; 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: 17632510

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF135 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 89

not providedTotal: 42

RNF135-related disorderTotal: 11

Macrocephaly, macrosomia, facial dysmorphism syndromeTotal: 4

Chromosome 17q11.2 deletion syndrome, 1.4MbTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032322.4. 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				15 clinvar		15
missense			78 clinvar	15 clinvar	1 clinvar	94
nonsense			3 clinvar			3
start loss						0
frameshift	1 clinvar		5 clinvar			6
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	88	30	1	120

Highest pathogenic variant AF is 0.000030400568

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032322.4	RefSeq	NP_115698.3	5	MANE Select
ENST00000328381.10	Ensembl	ENSP00000328340.5	5	MANE Select
NM_001184992.2	RefSeq	NP_001171921.1	6	Standard
NM_197939.2	RefSeq	NP_922921.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
Post-translational protein modification
TRAF6 mediated IRF7 activation
TRAF6 mediated NF-kB activation
DDX58/IFIH1-mediated induction of interferon-alpha/beta

Biological Process

protein ubiquitination
negative regulation of type I interferon production
positive regulation of interferon-beta production
innate immune response
regulation of innate immune response

Molecular Function

ubiquitin-protein transferase activity
protein binding
identical protein binding
ribonucleoprotein complex binding
metal ion binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328381
Coding exons: 5
Length: 31127
Individuals with no LoFs: 125643
Homozygous LoFs: 0
Heterozygous LoFs: 105
Defined: 125748
p: 0.000418

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0869	215	219	0.983	0.0000110	2765
Missense (PolyPhen)		41	47.116	0.87019		627
Synonymous	-0.356	93	88.7	1.05	0.00000447	893
Loss of Function	0.284	14	15.2	0.921	6.55e-7	173

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0014	0.0014	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00064	0.00064	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as an E2-dependent E3 ubiquitin-protein ligase, involved in innate immune defense against viruses. Ubiquitinates DDX58 and is required for full activation of the DDX58 signaling resulting in interferon beta production. {ECO:0000269|PubMed:19017631, ECO:0000269|PubMed:19484123}.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.833

Gene Damage Prediction

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