Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7

Summary

Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 (MONDO:0957261) is a disease caused by NAF1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NAF1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7
Mondo ID	MONDO:0957261
OMIM	620365
UMLS	C5830485
MedGen	1841121
GARD	0026800
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › pulmonary fibrosis › pulmonary fibrosis and/or bone marrow failure, telomere-related › pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7

Related subtypes (8): pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, pulmonary fibrosis and/or bone marrow failure, telomere-related, 5, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9

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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2501711	NM_138386.3(NAF1):c.984dup (p.Ser329fs)	NAF1	Pathogenic	no assertion criteria provided
2501712	NM_138386.3(NAF1):c.956_957del (p.Lys319fs)	NAF1	Pathogenic	no assertion criteria provided
3602679	NM_138386.3(NAF1):c.718-7A>G	NAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336641	NM_138386.3(NAF1):c.241C>G (p.Pro81Ala)	NAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376460	NM_138386.3(NAF1):c.227C>G (p.Ala76Gly)	NAF1	Uncertain significance	criteria provided, single submitter
4280006	NM_138386.3(NAF1):c.114_125del (p.Gly39_Pro42del)	NAF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NAF1	Strong	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7	2
TNIP1	Strong	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNIP1	Orphanet:536	Systemic lupus erythematosus

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
TNIP1	HGNC:16903	ENSG00000145901	Q15025	TNFAIP3-interacting protein 1	gencc,clinvar
NAF1	HGNC:25126	ENSG00000145414	Q96HR8	H/ACA ribonucleoprotein complex non-core subunit NAF1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNIP1	TNFAIP3-interacting protein 1	Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG.
NAF1	H/ACA ribonucleoprotein complex non-core subunit NAF1	RNA-binding protein required for the maturation of box H/ACA snoRNPs complex and ribosome biogenesis.

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)
TNIP1	Other/Unknown	no
NAF1	Other/Unknown	no		H/ACA_rnp_Gar1/Naf1, Transl_B-barrel_sf, Gar1/Naf1_Cbf5-bd_sf

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
blood	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1
gastrocnemius	1
popliteal artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNIP1	298	ubiquitous	marker	lower esophagus mucosa, blood, hindlimb stylopod muscle
NAF1	245	ubiquitous	marker	tibial artery, popliteal artery, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNIP1	3,304
NAF1	1,446

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNIP1	Q15025	8
NAF1	Q96HR8	1

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
Ovarian tumor domain proteases	1	278.5×	0.004	TNIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
box H/ACA snoRNP assembly	1	4213.0×	0.002	NAF1
snoRNA guided rRNA pseudouridine synthesis	1	2808.7×	0.002	NAF1
telomerase RNA stabilization	1	2106.5×	0.002	NAF1
RNA stabilization	1	1685.2×	0.002	NAF1
positive regulation of protein deubiquitination	1	1685.2×	0.002	TNIP1
positive regulation of telomere maintenance via telomere lengthening	1	1404.3×	0.002	NAF1
telomerase holoenzyme complex assembly	1	1404.3×	0.002	NAF1
telomerase RNA localization to Cajal body	1	1203.7×	0.002	NAF1
MyD88-dependent toll-like receptor signaling pathway	1	468.1×	0.005	TNIP1
positive regulation of telomere maintenance via telomerase	1	366.4×	0.006	NAF1
ribosome biogenesis	1	312.1×	0.007	NAF1
leukocyte cell-cell adhesion	1	234.1×	0.008	TNIP1
negative regulation of viral genome replication	1	187.2×	0.009	TNIP1
glycoprotein biosynthetic process	1	168.5×	0.010	TNIP1
defense response	1	108.0×	0.013	TNIP1
negative regulation of ERK1 and ERK2 cascade	1	108.0×	0.013	TNIP1
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.016	TNIP1
positive regulation of inflammatory response	1	72.6×	0.018	TNIP1
translation	1	51.4×	0.023	TNIP1
cellular response to lipopolysaccharide	1	49.0×	0.023	TNIP1
inflammatory response	1	18.9×	0.057	TNIP1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.136	TNIP1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TNIP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NAF1	1	2
TNIP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	NAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NAF1	7	Binding:7

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	NAF1

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	1	NAF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TNIP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNIP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.