SKIC3

protein-coding

SKI3 subunit of superkiller complex, the group of SKI complex subunits|Tetratricopeptide repeat domain containing

Gene summary

This gene encodes a protein with twenty tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Mutations in this gene are associated with trichohepatoenteric syndrome. [provided by RefSeq, Jul 2010]

Previous symbols:

KIAA0372
TTC37

MANE transcript

NM_014639.4

Inheritance

ClinVar variants

P:186U:477B:454

Top phenotype

Trichohepatoenteric syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr5:95,461,755-95,555,050

External References & Databases

Ensembl (ENSG00000198677)

Transcript & Mutation Effects

hg38 • Region Span ~93.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

trichohepatoenteric syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024541

Submitter: G2P

trichohepatoenteric syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024541

Submitter: PanelApp Australia

trichohepatoenteric syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024541

Submitter: Ambry Genetics

trichohepatoenteric syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024541

Submitter: ClinGen

The *SKIC3* gene is located on chromosome 5 at 5q15 and encodes for Superkiller complex protein 3 (SKIC3) protein. SKIC3 protein, which is the main and largest scaffolding subunit, forms a SKI complex with SKIC2 helicase protein and two SKIC8 protein subunits. SKI complex assists the RNA-degrading exosome during the mRNA decay and quality-control pathways. *SKIC3* was first reported in relation to autosomal recessive trichohepatoenteric syndrome (THES) 1 in 2010 (Hartley et al., PMID: 20176027). THES is characterized by intractable diarrhea (usually during neonatal period, seen in almost all affected children), wooly hair (seen in most children), intrauterine growth restriction, facial dysmorphism, short stature, immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies (Fabre et al 2018, PMID: 29334452). Nine different variants (nonsense, frameshift, missense) in *SKIC3* (previously known as TTC37) that were found in 12 children from 11 unrelated families are included in this curation (Hartley et al., 2010 PMID: 20176027; Chong et al., 2015 PMID: 25976726; Bourgeois et al., 2018 PMID: 29527791). This gene-disease relationship is also supported by biochemical function, gene expression, protein interaction studies (Tomecki et al., 2023 PMID:37384835; Fabre et al., 2010 PMID: 21120949; Kögel et al., 2022 PMID: 35120588). In summary, the *SKIC3* gene is definitively associated with autosomal recessive trichohepatoenteric syndrome (THES) 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic GCEP on the meeting date April 23rd, 2024 (SOP Version 10).

trichohepatoenteric syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024541

Submitter: Labcorp Genetics (formerly Invitae)

trichohepatoenteric syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009105

Submitter: Orphanet

Clinical Genomic Database (CGD)

Trichohepatoenteric syndrome 1AR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal

Intervention: Allergy/Immunology/Infectious; Gastrointestinal

Rationale: Individuals may also have immunodeficiency, and may benefit from prophylaxis and early and aggressive treatment of infections; Intractable diarrhea in infancy may require total parenteral nutrition; Patients may require hepatic transplant

Comments: The condition may be clinically recognizable, and prognosis may be poor in some individuals despite optimal therapy

Refs: 7073301; 8021782; 9021008; 9481629; 14521564; 15069414; 17236206; 17318842; 20176027; 21120949

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SKIC3 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1393

Inborn genetic diseasesTotal: 193

not specifiedTotal: 93

Trichohepatoenteric syndrome 1Total: 76

SKIC3-related disorderTotal: 52

TTC37-related disordersTotal: 16

Trichohepatoenteric syndromeTotal: 14

Fetal anomalies with a likely genetic causeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014639.4. 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			6 clinvar	410 clinvar	2 clinvar	418
missense		4 clinvar	460 clinvar	40 clinvar	2 clinvar	506
nonsense	44 clinvar	13 clinvar				57
start loss						0
frameshift	59 clinvar	16 clinvar	1 clinvar			76
splice donor/acceptor (+/-2bp)	3 clinvar	47 clinvar	10 clinvar			60
Total	106	80	477	450	4	1117

Highest pathogenic variant AF is 0.00014135223

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014639.4	RefSeq	NP_055454.1	40	MANE Select
ENST00000358746.7	Ensembl	ENSP00000351596.3	40	MANE Select
ENST00000505578.5	Ensembl	ENSP00000423141.1	4	Standard
ENST00000513232.2	Ensembl	ENSP00000422749.2	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA degradation - Homo sapiens (human)
Metabolism of RNA
mRNA decay by 3, to 5, exoribonuclease
Deadenylation-dependent mRNA decay

Biological Process

exonucleolytic nuclear-transcribed mRNA catabolic process involved in deadenylation-dependent decay

Molecular Function

protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
transcriptionally active chromatin

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358746
Coding exons: 40
Length: 91113
Individuals with no LoFs: 125505
Homozygous LoFs: 0
Heterozygous LoFs: 243
Defined: 125748
p: 0.000967

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.482	746	784	0.952	0.0000384	10183
Missense (PolyPhen)		206	235.66	0.87415		3120
Synonymous	0.0231	287	288	0.998	0.0000145	2907
Loss of Function	3.36	62	97.9	0.634	0.00000468	1253

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00046	0.00046	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.0028	0.0028	notable
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00066	0.00066	rare
South Asian	0.0023	0.0023	notable
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the SKI complex which is thought to be involved in exosome-mediated RNA decay and associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C).;

Recessive Scores

pRec: 0.0888

Intolerance Scores

LoFtool: 0.944
RVIS EVS: 0.06
RVIS percentile EVS: 58.01

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.776

Gene Damage Prediction

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