Silver-Russell syndrome 5

Summary

Silver-Russell syndrome 5 (MONDO:0020795) is a disease caused by HMGA2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: HMGA2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Silver-Russell syndrome 5
Mondo ID	MONDO:0020795
OMIM	618908
UMLS	C5394456
MedGen	1713787
GARD	0018465
Is cancer (heuristic)	no

Also known as: SILVER-RUSSELL SYNDROME 5 · Silver-Russell syndrome 5 · SRS5

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Silver-Russell syndrome › Silver-Russell syndrome 5

Related subtypes (10): Russell-silver syndrome, X-linked, Silver-Russell syndrome 3, silver-Russell syndrome due to 7p11.2p13 microduplication, silver-Russell syndrome due to an imprinting defect of 11p15, silver-Russell syndrome due to 11p15 microduplication, silver-Russell syndrome due to maternal uniparental disomy of chromosome 11, silver-Russell syndrome due to maternal uniparental disomy of chromosome 7, Silver-Russell syndrome 1, silver-russell syndrome 2, silver-russell syndrome 4

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

18 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 6 pathogenic, 4 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679403	NM_003483.6(HMGA2):c.47dup (p.Gln18fs)	HMGA2	Pathogenic	criteria provided, single submitter
253034	NM_003483.6(HMGA2):c.193C>T (p.Gln65Ter)	HMGA2	Pathogenic	criteria provided, single submitter
253035	NM_003483.6(HMGA2):c.189del (p.Ala64fs)	HMGA2	Pathogenic	no assertion criteria provided
3234118	NM_003483.6(HMGA2):c.138_141delinsCT (p.Lys46fs)	HMGA2	Pathogenic	criteria provided, single submitter
4755469	Single allele	HMGA2	Pathogenic	criteria provided, single submitter
917504	NM_003483.6(HMGA2):c.283-6_283del	HMGA2	Pathogenic	no assertion criteria provided
1705396	NM_003483.6(HMGA2):c.44_48del (p.Ala15fs)	HMGA2	Likely pathogenic	criteria provided, single submitter
4294469	NM_003483.6(HMGA2):c.52_56del (p.Gln18fs)	HMGA2	Likely pathogenic	criteria provided, single submitter
4531432	NM_003483.6(HMGA2):c.112-2A>G	HMGA2	Likely pathogenic	criteria provided, single submitter
4688022	NM_003483.6(HMGA2):c.112-1G>A	HMGA2	Likely pathogenic	criteria provided, single submitter
3235055	GRCh38/hg38 12q14.2-15(chr12:63871239-67314524)	C12orf56	Uncertain significance	criteria provided, single submitter
2444041	NM_003483.6(HMGA2):c.111+6T>A	HMGA2	Uncertain significance	criteria provided, single submitter
3068339	NM_003483.6(HMGA2):c.249+3_249+6del	HMGA2	Uncertain significance	criteria provided, single submitter
3068509	NM_003483.6(HMGA2):c.198+1G>A	HMGA2	Uncertain significance	criteria provided, single submitter
4056712	NM_003483.6(HMGA2):c.111+4A>G	HMGA2	Uncertain significance	criteria provided, single submitter
4077412	NM_003483.6(HMGA2):c.187G>A (p.Ala63Thr)	HMGA2	Uncertain significance	no assertion criteria provided
917507	NM_003483.6(HMGA2):c.303del (p.Ser102fs)	HMGA2	Uncertain significance	criteria provided, single submitter
768565	NM_003483.6(HMGA2):c.199-8A>G	HMGA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
HMGA2	Definitive	Autosomal dominant	Silver-Russell syndrome 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMGA2	Orphanet:276148	Benign epithelial tumor of salivary glands
HMGA2	Orphanet:397590	Silver-Russell syndrome due to a point mutation
HMGA2	Orphanet:94063	12q14 microdeletion syndrome
HMGA2	Orphanet:99970	Dedifferentiated liposarcoma
HMGA2	Orphanet:99971	Well-differentiated liposarcoma

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
HMGA2	HGNC:5009	ENSG00000149948	P52926	High mobility group protein HMGI-C	gencc,clinvar
C12orf56	HGNC:26967	ENSG00000185306	Q8IXR9	Uncharacterized protein C12orf56	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMGA2	High mobility group protein HMGI-C	Functions as a transcriptional regulator.

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)
HMGA2	Other/Unknown	no		HMGA, HMGI/Y_DNA-bd_CS, AT_hook_DNA-bd_motif
C12orf56	Other/Unknown	no		DUF4551

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
embryo	1
stromal cell of endometrium	1
sural nerve	1
lower esophagus mucosa	1
primordial germ cell in gonad	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HMGA2	149	ubiquitous	marker	sural nerve, embryo, stromal cell of endometrium
C12orf56	141	tissue_specific	marker	sperm, lower esophagus mucosa, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGA2	219
C12orf56	170

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C12orf56	Q8IXR9	71.54
HMGA2	P52926	65.46

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
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	671.8×	0.001	HMGA2

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
mesodermal-endodermal cell signaling	1	16852.0×	0.003	HMGA2
regulation of growth hormone secretion	1	5617.3×	0.003	HMGA2
negative regulation of intracellular steroid hormone receptor signaling pathway	1	4213.0×	0.003	HMGA2
positive regulation of cell proliferation in bone marrow	1	4213.0×	0.003	HMGA2
positive regulation of epithelial cell proliferation involved in lung morphogenesis	1	2407.4×	0.003	HMGA2
oncogene-induced cell senescence	1	2407.4×	0.003	HMGA2
mesenchymal cell differentiation	1	2106.5×	0.003	HMGA2
lung epithelium development	1	2106.5×	0.003	HMGA2
negative regulation of double-strand break repair via nonhomologous end joining	1	2106.5×	0.003	HMGA2
fat pad development	1	1685.2×	0.003	HMGA2
negative regulation of single stranded viral RNA replication via double stranded DNA intermediate	1	1532.0×	0.003	HMGA2
mesodermal cell differentiation	1	1532.0×	0.003	HMGA2
negative regulation of astrocyte differentiation	1	1532.0×	0.003	HMGA2
regulation of stem cell population maintenance	1	1404.3×	0.003	HMGA2
cell proliferation in forebrain	1	1296.3×	0.003	HMGA2
host-mediated suppression of viral transcription	1	1296.3×	0.003	HMGA2
positive regulation of protein serine/threonine kinase activity	1	1296.3×	0.003	HMGA2
negative regulation of DNA binding	1	1123.5×	0.003	HMGA2
chondrocyte proliferation	1	1053.2×	0.003	HMGA2
regulation of cell cycle process	1	991.3×	0.003	HMGA2
negative regulation of receptor signaling pathway via JAK-STAT	1	887.0×	0.003	HMGA2
chromosome condensation	1	842.6×	0.003	HMGA2
epithelial tube branching involved in lung morphogenesis	1	842.6×	0.003	HMGA2
astrocyte differentiation	1	766.0×	0.003	HMGA2
adrenal gland development	1	674.1×	0.003	HMGA2
pituitary gland development	1	648.1×	0.003	HMGA2
negative regulation of cellular senescence	1	648.1×	0.003	HMGA2
positive regulation of stem cell proliferation	1	526.6×	0.004	HMGA2
endodermal cell differentiation	1	495.6×	0.004	HMGA2
positive regulation of multicellular organism growth	1	495.6×	0.004	HMGA2

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
HMGA2	0	0
C12orf56	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	HMGA2, C12orf56

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)
HMGA2	0	—
C12orf56	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.