PFN1

protein-coding

profilin 1, the group of Profilins

Gene summary

This gene encodes a member of the profilin family of small actin-binding proteins. The encoded protein plays an important role in actin dynamics by regulating actin polymerization in response to extracellular signals. Deletion of this gene is associated with Miller-Dieker syndrome, and the encoded protein may also play a role in Huntington disease. Multiple pseudogenes of this gene are located on chromosome 1. [provided by RefSeq, Jul 2012]

MANE transcript

NM_005022.4

Inheritance

ClinVar variants

P:4U:44B:24

Top phenotype

Amyotrophic lateral sclerosis 18

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:4,945,652-4,949,061

External References & Databases

Ensembl (ENSG00000108518)

Transcript & Mutation Effects

hg38 • Region Span ~3.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 18DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013891

Submitter: ClinGen

PFN1 was first reported in relation to autosomal dominant ALS18 in 2012 (Wu et al, 2012; PMID: 22801503). At least 7 variants (all missense) with a possible association with ALS18 have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 12 probands with ALS in 6 publications (PMIDs: 22801503, 23141414, 23428184, 25499087, 31802421, 31401564). Variants in this gene have been found to segregate with disease in at least 17 additional family members. This gene-disease association is supported by animal models( PMIDs: 28040732, 27681617) and functional assays in patient (PMID: 31444357) and non-patient cells (PMIDs: 22801503, 26908597, 31444357). The mechanism for disease is currently unclear but is suspected to involve heterozygous toxic gain-of-function, a dominant-negative mechanism, or a loss-of-function mechanism, though the former appears most likely (Wu et al, 2012 - PMID: 22801503; Yang et al, 2016 - PMID: 27681617; Tanaka et al, 2016 - PMID: 26908597; Fil et al, 2017 - PMID: 28040732; Giampetruzzi et al, 2019 - PMID: 31444357). In summary, there is currently definitive evidence that has been replicated over time to support this gene-disease relationship, and no convincing contradictory evidence has emerged. Of note, one additional variant (a NMD- frameshift variant) has been reported in at least 3 reportedly unrelated families (though they may be distantly related) with autosomal dominant Paget disease of bone in 2 publications (Merlotti et al, 2020 - PMID 32392277; Scotto di Carlo et al, 2020 - PMID: 31991009). Due to the differences in apparent molecular mechanism and phenotype his gene-disease relationship was not assessed as part of the PFN1-ALS curation.

amyotrophic lateral sclerosis type 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013891

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosis type 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013891

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosis type 18MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013891

Submitter: Ambry Genetics

amyotrophic lateral sclerosis type 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013891

Submitter: PanelApp Australia

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 18AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22801503; 23141414

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PFN1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 77

PFN1-related disorderTotal: 11

Inborn genetic diseasesTotal: 10

Amyotrophic lateral sclerosis type 18Total: 8

not specifiedTotal: 6

Amyotrophic lateral sclerosisTotal: 2

NeurodegenerationTotal: 1

PAGET DISEASE OF BONE 7, EARLY-ONSETTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005022.4. 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			3 clinvar	20 clinvar	1 clinvar	24
missense	3 clinvar		38 clinvar	3 clinvar		44
nonsense						0
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	3	1	44	23	1	72

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005022.4	RefSeq	NP_005013.1	3	MANE Select
ENST00000225655.6	Ensembl	ENSP00000225655.5	3	MANE Select
NM_001375991.1	RefSeq	NP_001362920.1	2	Standard
ENST00000572383.1	Ensembl	ENSP00000460363.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pfn1	Danio rerio	Structure: convergent extension involved in gastrulation Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

pfn1

Danio rerio

Structure: convergent extension involved in gastrulation

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salmonella infection - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Shigellosis - Homo sapiens (human)
Association Between Physico-Chemical Features and Toxicity Associated Pathways

Biological Process

neural tube closure
regulation of transcription by RNA polymerase II
positive regulation of epithelial cell migration
actin cytoskeleton organization
regulation of actin filament polymerization

Molecular Function

adenyl-nucleotide exchange factor activity
RNA binding
actin binding
actin monomer binding
protein binding

Cellular Component

nucleus
cytoplasm
cytosol
cytoskeleton
focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000225655
Coding exons: 3
Length: 3410
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.95	35	85.9	0.407	0.00000465	903
Missense (PolyPhen)		7	17.484	0.40036		232
Synonymous	-1.40	45	34.5	1.30	0.00000179	289
Loss of Function	1.93	0	4.36	0.00	1.84e-7	55

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR. {ECO:0000269|PubMed:18573880}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 18 (ALS18) [MIM:614808]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:22801503}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.260

Intolerance Scores

LoFtool: 0.175
RVIS EVS: -0.08
RVIS percentile EVS: 47.79

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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