Infantile liver failure syndrome 2

Summary

Infantile liver failure syndrome 2 (MONDO:0014659) is a disease caused by NBAS (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NBAS (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 126

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile liver failure syndrome 2
Mondo ID	MONDO:0014659
OMIM	616483
NCIT	C158135
UMLS	C3809651
MedGen	815981
GARD	0013113
Is cancer (heuristic)	no

Also known as: ILFS2 · infantile liver failure caused by mutation in NBAS · infantile liver failure syndrome 2 · infantile liver failure syndrome type 2 · NBAS infantile liver failure

Data availability: 126 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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 2

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

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

126 retrieved; paginated sample, class counts are floors:

29 likely pathogenic, 24 conflicting classifications of pathogenicity, 23 pathogenic/likely pathogenic, 20 uncertain significance, 14 benign, 12 pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1442652	NM_015909.4(NBAS):c.1A>C (p.Met1Leu)	LOC129933155	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
838205	NM_015909.4(NBAS):c.17C>A (p.Ser6Ter)	LOC129933155	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032709	NM_015909.4(NBAS):c.5262del (p.Phe1754fs)	NBAS	Pathogenic	criteria provided, single submitter
1076261	NM_015909.4(NBAS):c.2827G>T (p.Glu943Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1172780	NM_015909.4(NBAS):c.4288C>T (p.Gln1430Ter)	NBAS	Pathogenic	criteria provided, single submitter
1323328	NM_015909.4(NBAS):c.1858A>T (p.Lys620Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1333991	NM_015909.4(NBAS):c.513+2T>C	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1335898	NM_015909.4(NBAS):c.1213C>T (p.Arg405Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1373796	NM_015909.4(NBAS):c.2389C>T (p.Arg797Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427718	NM_015909.4(NBAS):c.1366C>T (p.Arg456Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441232	NM_015909.4(NBAS):c.3842dup (p.Gln1282fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448431	NM_015909.4(NBAS):c.169C>T (p.Arg57Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452384	NM_015909.4(NBAS):c.2802G>A (p.Trp934Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1456602	NM_015909.4(NBAS):c.4336C>T (p.Arg1446Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457346	NM_015909.4(NBAS):c.3316C>T (p.Gln1106Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693290	NM_015909.4(NBAS):c.3010C>T (p.Arg1004Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1723648	NM_015909.4(NBAS):c.4753C>T (p.Arg1585Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1942208	NM_015909.4(NBAS):c.4332_4333insT (p.Leu1445fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1946443	NM_015909.4(NBAS):c.5176del (p.Leu1726fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1958400	NM_015909.4(NBAS):c.354dup (p.Thr119fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
204580	NM_015909.4(NBAS):c.558_560del (p.Ile187del)	NBAS	Pathogenic	no assertion criteria provided
2163359	NM_015909.4(NBAS):c.5983C>T (p.Arg1995Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218416	NM_015909.4(NBAS):c.409C>T (p.Arg137Trp)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441821	NM_015909.4(NBAS):c.4255del (p.Ser1419fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
2988958	NM_015909.4(NBAS):c.3706C>T (p.Arg1236Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584473	NM_015909.4(NBAS):c.6448_6449del (p.Asp2149_Ile2150insTer)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584475	NM_015909.4(NBAS):c.5883_5884dup (p.Leu1962fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584486	NM_015909.4(NBAS):c.2591dup (p.Leu864fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584489	NM_015909.4(NBAS):c.425dup (p.Tyr142Ter)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421958	NM_015909.4(NBAS):c.6316del (p.Arg2106fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 4 · 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
NBAS	Strong	Autosomal recessive	infantile liver failure syndrome 2	8
RINT1	Strong	Autosomal recessive	infantile liver failure syndrome 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NBAS	Orphanet:391677	Short stature-optic atrophy-Pelger-Huët anomaly syndrome
NBAS	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
RINT1	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
PTPRO	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NBAS	HGNC:15625	ENSG00000151779	A2RRP1	NBAS subunit of NRZ tethering complex	gencc,clinvar
RINT1	HGNC:21876	ENSG00000135249	Q6NUQ1	RAD50-interacting protein 1	gencc
PTPRO	HGNC:9678	ENSG00000151490	Q16827	Receptor-type tyrosine-protein phosphatase O	clinvar
PTPRU	HGNC:9683	ENSG00000060656	Q92729	Receptor-type tyrosine-protein phosphatase U	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NBAS	NBAS subunit of NRZ tethering complex	Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; 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.
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.
PTPRO	Receptor-type tyrosine-protein phosphatase O	Possesses tyrosine phosphatase activity.
PTPRU	Receptor-type tyrosine-protein phosphatase U	Tyrosine-protein phosphatase which dephosphorylates CTNNB1.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	2	42.0×	0.003
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NBAS	Scaffold/PPI	no		Quino_amine_DH_bsu, Sec39_domain, WD40/YVTN_repeat-like_dom_sf
RINT1	Other/Unknown	no		RINT1_Tip20, EXOC6PINT-1/Sec15/Tip20_C_dom2
PTPRO	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
PTPRU	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, MAM_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
primordial germ cell in gonad	1
ventricular zone	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibia	1
cortical plate	1
metanephric glomerulus	1
renal glomerulus	1
ectocervix	1
endocervix	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NBAS	293	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, ventricular zone
RINT1	259	ubiquitous	marker	tibia, male germ line stem cell (sensu Vertebrata) in testis, body of pancreas
PTPRO	214	broad	marker	renal glomerulus, metanephric glomerulus, cortical plate
PTPRU	239	ubiquitous	marker	endocervix, olfactory segment of nasal mucosa, ectocervix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RINT1	2,398
PTPRO	1,520
NBAS	1,134
PTPRU	206

Intra-cohort edges

A	B	Sources
NBAS	RINT1	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPRO	Q16827	2
PTPRU	Q92729	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RINT1	Q6NUQ1	85.97
NBAS	A2RRP1	74.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (4 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 4 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	2	55.4×	0.003	NBAS, RINT1
Signaling by NTRK3 (TRKC)	1	285.5×	0.012	PTPRO
Signaling by SCF-KIT	1	62.1×	0.037	PTPRU
Golgi-to-ER retrograde transport	1	33.2×	0.052	NBAS
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.053	NBAS
Membrane Trafficking	1	9.3×	0.110	NBAS
Vesicle-mediated transport	1	8.7×	0.110	NBAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	2	168.5×	0.002	NBAS, RINT1
slit diaphragm assembly	1	2106.5×	0.004	PTPRO
negative regulation of retinal ganglion cell axon guidance	1	2106.5×	0.004	PTPRO
negative regulation of canonical Wnt signaling pathway	2	58.9×	0.004	PTPRO, PTPRU
regulation of glomerular filtration	1	1053.2×	0.005	PTPRO
negative regulation of glomerular filtration	1	1053.2×	0.005	PTPRO
cell surface receptor protein tyrosine phosphatase signaling pathway	1	526.6×	0.007	PTPRU
regulation of ER to Golgi vesicle-mediated transport	1	526.6×	0.007	RINT1
negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	468.1×	0.007	NBAS
homotypic cell-cell adhesion	1	421.3×	0.007	PTPRU
podocyte differentiation	1	351.1×	0.007	PTPRO
glomerulus development	1	324.1×	0.007	PTPRO
positive regulation of cell-cell adhesion mediated by cadherin	1	324.1×	0.007	PTPRU
protein transport	2	21.9×	0.007	NBAS, RINT1
negative regulation of cell-substrate adhesion	1	263.3×	0.008	PTPRO
nuclear-transcribed mRNA catabolic process	1	191.5×	0.011	NBAS
regulation of synapse organization	1	162.0×	0.012	PTPRO
animal organ regeneration	1	150.5×	0.012	PTPRU
monocyte chemotaxis	1	145.3×	0.012	PTPRO
protein localization to cell surface	1	123.9×	0.013	PTPRU
mitotic G2 DNA damage checkpoint signaling	1	110.9×	0.013	RINT1
lamellipodium assembly	1	110.9×	0.013	PTPRO
response to glucocorticoid	1	81.0×	0.018	PTPRU
negative regulation of neuron projection development	1	59.3×	0.023	PTPRO
protein dephosphorylation	1	55.4×	0.024	PTPRU
cell morphogenesis	1	39.4×	0.032	PTPRO
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.036	RINT1
neuron projection development	1	30.5×	0.038	PTPRU
negative regulation of cell migration	1	27.9×	0.040	PTPRU
axon guidance	1	22.6×	0.048	PTPRO

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NBAS	0	0
RINT1	0	0
PTPRO	0	0
PTPRU	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PTPRO	7	Binding:7
NBAS	1	Binding:1
PTPRU	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPRO	3.1.3.48	protein-tyrosine-phosphatase
PTPRU	3.1.3.48	protein-tyrosine-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	PTPRO, PTPRU
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	NBAS, RINT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NBAS	1	—
RINT1	0	—
PTPRO	7	—
PTPRU	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.