GeneBe

GSN

protein-coding

gelsolin, the group of Gelsolin/villins

Gene summary

The protein encoded by this gene binds to the "plus" ends of actin monomers and filaments to prevent monomer exchange. The encoded calcium-regulated protein functions in both assembly and disassembly of actin filaments. Defects in this gene are a cause of familial amyloidosis Finnish type (FAF). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_198252.3

Inheritance

AD, AR, SD

ClinVar variants

P:6U:432B:242

Top phenotype

Amyloidosis, Finnish type

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr9:121,207,794-121,332,843

External References & Databases

Ensembl (ENSG00000148180)NCBI Gene (2934)OMIM (137350)HGNC:4620GenCCUniProt (P06396)AlphaFoldClinVar (GSN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~125.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Finnish type amyloidosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007097

Submitter: Orphanet

Finnish type amyloidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007097

Submitter: G2P

Finnish type amyloidosisSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007097

Submitter: PanelApp Australia

Finnish type amyloidosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007097

Submitter: Labcorp Genetics (formerly Invitae)

Finnish type amyloidosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007097

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Amyloidosis, Finnish typeAD

Manifestation: Cardiovascular; Dermatologic; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular

Rationale: Individuals with cardiac conduction disease have been described, and surveillance (eg, with electocardiogram) may allow early management (eg, with pacemaker)

Comments: Recessive disease has been reported as resulting in a more severe phenotype

Refs: 4543600; 2153578; 2176164; 1322359; 1311149; 1315718; 8395367; 8684801; 11754099; 16258946; 22068858; 22622774Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GSN variants in ClinVar

6 Conditions Cataloged
not providedTotal: 793
Finnish type amyloidosisTotal: 235
Inborn genetic diseasesTotal: 195
GSN-related disorderTotal: 123
not specifiedTotal: 46
GSN-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198252.3. 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.

EffectPLPVUSLBBSum
synonymous
8
clinvar
178
clinvar
1
clinvar
 187
missense
3
clinvar
3
clinvar
375
clinvar
58
clinvar
4
clinvar
 443
nonsense
10
clinvar
 10
start loss
1
clinvar
 1
frameshift
19
clinvar
 19
splice donor/acceptor (+/-2bp)
19
clinvar
1
clinvar
 20
Total334322375680

Highest pathogenic variant AF is 0.0000049566665

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 611 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_198252.3RefSeqNP_937895.116MANE Select
ENST00000432226.7EnsemblENSP00000404226.216MANE Select
NM_000177.5RefSeqNP_000168.117Standard
NM_001127662.2RefSeqNP_001121134.116Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Fc gamma R-mediated phagocytosis - Homo sapiens (human)
  • Regulation of actin cytoskeleton - Homo sapiens (human)
  • Viral carcinogenesis - Homo sapiens (human)
  • Regulation of Actin Cytoskeleton
  • Senescence and Autophagy in Cancer

Biological Process

  • phagocytosis, engulfment
  • aging
  • positive regulation of gene expression
  • oligodendrocyte development
  • striated muscle atrophy

Molecular Function

  • actin binding
  • calcium ion binding
  • protein binding
  • myosin II binding
  • actin filament binding

Cellular Component

  • ruffle
  • podosome
  • extracellular region
  • extracellular space
  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000373818
Coding exons
17
Length
125050
Individuals with no LoFs
125664
Homozygous LoFs
0
Heterozygous LoFs
84
Defined
125748
p
0.000334
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9624014590.8740.00003085034
Missense (PolyPhen)156189.860.821672090
Synonymous0.4271891970.9610.00001461604
Loss of Function2.372338.90.5910.00000190433

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000460.00046rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000600.00060rare
Finnish00.0absent
European (Non-Finnish)0.000370.00037rare
South Asian0.000200.00020rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed. Plays a role in ciliogenesis. {ECO:0000269|PubMed:20393563}.;
Disease
DISEASE: Amyloidosis 5 (AMYL5) [MIM:105120]: A hereditary generalized amyloidosis due to gelsolin amyloid deposition. It is typically characterized by cranial neuropathy and lattice corneal dystrophy. Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure. {ECO:0000269|PubMed:1338910, ECO:0000269|PubMed:2176481}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.752

Intolerance Scores

LoFtool
0.888
RVIS EVS
0.61
RVIS percentile EVS
82.94

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.981

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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