Microcephaly, short stature, and impaired glucose metabolism 1

Summary

Microcephaly, short stature, and impaired glucose metabolism 1 (MONDO:0000208) is a disease caused by TRMT10A (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TRMT10A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly, short stature, and impaired glucose metabolism 1
Mondo ID	MONDO:0000208
OMIM	616033
UMLS	C4014997
MedGen	863434
GARD	0018459
Is cancer (heuristic)	no

Also known as: microcephaly, short stature, and impaired glucose metabolism · microcephaly, short stature, and impaired glucose metabolism 1 · MSSGM · MSSGM1

Data availability: 20 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › microcephaly, short stature, and impaired glucose metabolism › microcephaly, short stature, and impaired glucose metabolism 1

Related subtypes (1): microcephaly, short stature, and impaired glucose metabolism 2

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

20 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 5 pathogenic, 3 uncertain significance, 3 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332859	NM_001134665.3(TRMT10A):c.23dup (p.Phe9fs)	TRMT10A	Pathogenic	criteria provided, multiple submitters, no conflicts
1454256	NM_001134665.3(TRMT10A):c.193C>T (p.Arg65Ter)	TRMT10A	Pathogenic	criteria provided, multiple submitters, no conflicts
156229	NM_001134665.3(TRMT10A):c.379C>T (p.Arg127Ter)	TRMT10A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156230	NM_001134665.3(TRMT10A):c.616G>A (p.Gly206Arg)	TRMT10A	Pathogenic	criteria provided, multiple submitters, no conflicts
1690555	NM_001134665.3(TRMT10A):c.226C>T (p.Arg76Ter)	TRMT10A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444063	NM_001134665.3(TRMT10A):c.346A>T (p.Lys116Ter)	TRMT10A	Pathogenic	criteria provided, single submitter
3377077	NM_001134665.3(TRMT10A):c.151C>T (p.Gln51Ter)	TRMT10A	Pathogenic	criteria provided, single submitter
1709365	NM_001134665.3(TRMT10A):c.41del (p.Asn14fs)	TRMT10A	Likely pathogenic	criteria provided, single submitter
4077707	NM_001134665.3(TRMT10A):c.405_406del (p.Leu136fs)	TRMT10A	Likely pathogenic	criteria provided, single submitter
4531959	NM_001134665.3(TRMT10A):c.496-1G>A	TRMT10A	Likely pathogenic	criteria provided, single submitter
4531960	NM_001134665.3(TRMT10A):c.420+1G>A	TRMT10A	Likely pathogenic	criteria provided, single submitter
4845348	NM_001134665.3(TRMT10A):c.148_152del (p.Lys50fs)	TRMT10A	Likely pathogenic	criteria provided, single submitter
4849284	NM_001134665.3(TRMT10A):c.206del (p.Arg69fs)	TRMT10A	Likely pathogenic	criteria provided, single submitter
974899	NM_001134665.3(TRMT10A):c.697_698delinsTA (p.Pro233Ter)	TRMT10A	Likely pathogenic	criteria provided, single submitter
1336009	NM_001134665.3(TRMT10A):c.149A>T (p.Lys50Ile)	TRMT10A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
437057	NM_001134665.3(TRMT10A):c.398G>A (p.Arg133Gln)	TRMT10A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
720573	NM_001134665.3(TRMT10A):c.665C>T (p.Ala222Val)	TRMT10A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029187	NM_001134665.3(TRMT10A):c.388G>A (p.Ala130Thr)	TRMT10A	Uncertain significance	criteria provided, single submitter
1029188	NM_001134665.3(TRMT10A):c.388G>T (p.Ala130Ser)	TRMT10A	Uncertain significance	criteria provided, single submitter
984716	NM_001134665.3(TRMT10A):c.348G>C (p.Lys116Asn)	TRMT10A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TRMT10A	Definitive	Autosomal recessive	microcephaly, short stature, and impaired glucose metabolism 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRMT10A	Orphanet:391408	Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRMT10A	HGNC:28403	ENSG00000145331	Q8TBZ6	tRNA methyltransferase 10 homolog A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRMT10A	tRNA methyltransferase 10 homolog A	S-adenosyl-L-methionine-dependent guanine N(1)-methyltransferase that catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRMT10A	Enzyme (other)	yes	2.1.1.221	tRNA_m1G_MeTrfase_euk, TRM10/TRM10A, MT_TRM10-typ

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRMT10A	201	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRMT10A	1,211

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRMT10A	Q8TBZ6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
tRNA modification in the nucleus and cytosol	1	292.8×	0.003	TRMT10A

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
tRNA N1-guanine methylation	1	5617.3×	4e-04	TRMT10A
tRNA methylation	1	581.1×	0.002	TRMT10A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TRMT10A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRMT10A	2.1.1.221	tRNA (guanine9-N1)-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TRMT10A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
TRMT10A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.