Infantile liver failure syndrome 3

Summary

Infantile liver failure syndrome 3 (MONDO:0032844) is a disease caused by RINT1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RINT1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile liver failure syndrome 3
Mondo ID	MONDO:0032844
OMIM	618641
UMLS	C5231437
MedGen	1684678
GARD	0016483
Is cancer (heuristic)	no

Also known as: ILFS3

Data availability: 38 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › infantile liver failure › infantile liver failure syndrome 3

Related subtypes (3): acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, infantile liver failure syndrome 2, infantile liver failure syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

38 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 6 conflicting classifications of pathogenicity, 4 benign, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
599396	NM_021930.6(RINT1):c.1109T>C (p.Leu370Pro)	RINT1	Pathogenic	no assertion criteria provided
692227	NM_021930.6(RINT1):c.1333+1G>T	RINT1	Pathogenic	no assertion criteria provided
4526601	NM_021930.6(RINT1):c.1207_1210del (p.Asp403fs)	RINT1	Likely pathogenic	criteria provided, single submitter
1030776	NM_021930.6(RINT1):c.29C>A (p.Ser10Tyr)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1449407	NM_021930.6(RINT1):c.1555C>T (p.Arg519Ter)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241394	NM_021930.6(RINT1):c.1187A>G (p.Asn396Ser)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241407	NM_021930.6(RINT1):c.388G>A (p.Ala130Thr)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547947	NM_021930.6(RINT1):c.1333+1G>A	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
659053	NM_021930.6(RINT1):c.1256C>G (p.Pro419Arg)	RINT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1327123	NM_021930.6(RINT1):c.2096GAG[1] (p.Gly700del)	EFCAB10	Uncertain significance	criteria provided, single submitter
3594198	NM_021930.6(RINT1):c.2068-11delinsTTTGT	EFCAB10	Uncertain significance	criteria provided, single submitter
3594199	NM_021930.6(RINT1):c.2102C>T (p.Ala701Val)	EFCAB10	Uncertain significance	criteria provided, single submitter
410784	NM_021930.6(RINT1):c.2067+6_2067+9del	EFCAB10	Uncertain significance	criteria provided, multiple submitters, no conflicts
410799	NM_021930.6(RINT1):c.1940C>T (p.Ser647Leu)	EFCAB10	Uncertain significance	criteria provided, multiple submitters, no conflicts
646534	NM_021930.6(RINT1):c.2361G>A (p.Trp787Ter)	EFCAB10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001996	NM_021930.6(RINT1):c.1339C>T (p.Leu447Phe)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025153	NM_021930.6(RINT1):c.1120C>T (p.Arg374Trp)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1042688	NM_021930.6(RINT1):c.319T>G (p.Leu107Val)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327122	NM_021930.6(RINT1):c.604C>T (p.Gln202Ter)	RINT1	Uncertain significance	criteria provided, single submitter
1363651	NM_021930.6(RINT1):c.840-12T>A	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1777784	NM_021930.6(RINT1):c.1675T>C (p.Phe559Leu)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2294951	NM_021930.6(RINT1):c.1429G>C (p.Asp477His)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594196	NM_021930.6(RINT1):c.728T>G (p.Phe243Cys)	RINT1	Uncertain significance	criteria provided, single submitter
3594197	NM_021930.6(RINT1):c.1536A>C (p.Leu512Phe)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892287	NM_021930.6(RINT1):c.1180G>T (p.Asp394Tyr)	RINT1	Uncertain significance	criteria provided, single submitter
410803	NM_021930.6(RINT1):c.1609T>C (p.Cys537Arg)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
410809	NM_021930.6(RINT1):c.1756T>G (p.Ser586Ala)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
547946	NM_021930.6(RINT1):c.1853_1858del (p.Val618_Lys619del)	RINT1	Uncertain significance	criteria provided, single submitter
663180	NM_021930.6(RINT1):c.1855A>C (p.Lys619Gln)	RINT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
692228	NM_021930.6(RINT1):c.1102G>A (p.Ala368Thr)	RINT1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RINT1	Strong	Autosomal recessive	infantile liver failure syndrome 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RINT1	Orphanet:464724	Fever-associated acute infantile liver failure syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RINT1	HGNC:21876	ENSG00000135249	Q6NUQ1	RAD50-interacting protein 1	gencc,clinvar
EFCAB10	HGNC:34531	ENSG00000185055	A6NFE3	EF-hand calcium-binding domain-containing protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RINT1	RAD50-interacting protein 1	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RINT1	Other/Unknown	no		RINT1_Tip20, EXOC6PINT-1/Sec15/Tip20_C_dom2
EFCAB10	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EFC10

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibia	1
left testis	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RINT1	259	ubiquitous	marker	tibia, male germ line stem cell (sensu Vertebrata) in testis, body of pancreas
EFCAB10	132	broad	marker	right uterine tube, olfactory segment of nasal mucosa, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RINT1	2,398
EFCAB10	464

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RINT1	Q6NUQ1	85.97
EFCAB10	A6NFE3	83.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-dependent Golgi-to-ER retrograde traffic	1	110.9×	0.009	RINT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of ER to Golgi vesicle-mediated transport	1	2106.5×	0.002	RINT1
mitotic G2 DNA damage checkpoint signaling	1	443.5×	0.005	RINT1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	337.0×	0.005	RINT1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.009	RINT1
protein transport	1	43.9×	0.023	RINT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RINT1	0	0
EFCAB10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RINT1, EFCAB10

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RINT1	0	—
EFCAB10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.