SYNPO

protein-coding

synaptopodin

Gene summary

Synaptopodin is an actin-associated protein that may play a role in actin-based cell shape and motility. The name synaptopodin derives from the protein's associations with postsynaptic densities and dendritic spines and with renal podocytes (Mundel et al., 1997 [PubMed 9314539]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_007286.6

Inheritance

ClinVar variants

U:236B:78

Top phenotype

Nephrotic syndrome

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr5:150,601,080-150,659,207

External References & Databases

Ensembl (ENSG00000171992)

Transcript & Mutation Effects

hg38 • Region Span ~58.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

focal segmental glomerulosclerosisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100313

Submitter: ClinGen

SYNPO was first reported in relation to autosomal dominant glomerulopathy in 2010 (Dai et al., PMID: 19666657). Two variants (at the promoter site) that have been reported in 2 probands in one publication (PMID: 19666657) are included in this curation. A second publication details an affected individual with a homozygous missense variant, although heterozygous familial carriers are unaffected (PMID: 33615071). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression in podocytes, interaction with CD2AP, and a knockout model demonstrating conditionally stimulated nephrotic syndrome along with podocytes showing impaired actin filament reformation in vitro (PMIDs: 15841212, 16628251, 33615071). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date November 13, 2023 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYNPO variants in ClinVar

5 Conditions Cataloged

not providedTotal: 208

not specifiedTotal: 172

Nephrotic syndromeTotal: 1

Focal segmental glomerulosclerosis 8Total: 1

SYNPO-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007286.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	54 clinvar	7 clinvar	66
missense			229 clinvar	13 clinvar	4 clinvar	246
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	0	236	67	11	314

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007286.6	RefSeq	NP_009217.3	2	MANE Select
ENST00000307662.5	Ensembl	ENSP00000302139.4	2	MANE Select
NM_001109974.3	RefSeq	NP_001103444.1	1	Standard
NM_001166208.2	RefSeq	NP_001159680.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Primary Focal Segmental Glomerulosclerosis FSGS

Biological Process

visual learning
positive regulation of actin filament bundle assembly
regulation of long-term neuronal synaptic plasticity
modification of dendritic spine
postsynaptic modulation of chemical synaptic transmission

Molecular Function

actin binding
protein binding

Cellular Component

stress fiber
nucleus
bicellular tight junction
postsynaptic density
actin cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394243
Coding exons: 2
Length: 58141
Individuals with no LoFs: 125038
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125041
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.934	496	558	0.889	0.0000361	5930
Missense (PolyPhen)		174	226.14	0.76943		2400
Synonymous	0.501	238	248	0.960	0.0000174	2078
Loss of Function	4.19	3	26.1	0.115	0.00000169	276

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes. Seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.165

Intolerance Scores

LoFtool: 0.0129
RVIS EVS: -0.17
RVIS percentile EVS: 40.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.811

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium