PRPH

protein-coding

peripherin, the group of Intermediate filaments Type III

Gene summary

This gene encodes a cytoskeletal protein found in neurons of the peripheral nervous system. The encoded protein is a type III intermediate filament protein with homology to other cytoskeletal proteins such as desmin, and is a different protein that the peripherin found in photoreceptors. Mutations in this gene have been associated with susceptibility to amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

Previous symbols:

NEF4

MANE transcript

NM_006262.4

Inheritance

AD, AR

ClinVar variants

P:4U:90B:12

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr12:49,295,147-49,298,686

External References & Databases

Ensembl (ENSG00000135406)

Transcript & Mutation Effects

hg38 • Region Span ~3.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis type 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007103

Submitter: PanelApp Australia

amyotrophic lateral sclerosis type 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0007103

Submitter: PanelApp Australia

amyotrophic lateral sclerosisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*PRPH* was first reported in relation to amyotrophic lateral sclerosis 7(ALS) in 2004 (Leung et al., PMID: 15446584). This individual had a homozygous missense variant, Asp141Tyr, which has since been found to occur at a frequency of 0.3% (based on the total gnomADv2.1.1 non-neuro population) and is not considered plausibly causative of ALS for this curation. Since 2004 rare heterozygous variants have been identified in additional ALS patients and an autosomal dominant mechanism has been considered here. *PRPH* encodes peripherin, a neuronal-specific intermediate filament protein expressed predominantly in the peripheral nervous system. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 plausibly causative, rare variants have been reported in relation to ALS (including frameshift and missense variants). Variants in this gene have been reported in at least 4 probands in 3 publications (PMIDs: 15322088, 25299611, 26742954). Experimentally, this gene-disease relationship is supported by its expression in the nerous system (PMID: 3339087) and the fact that it is a major component found in inclusions of patients with ALS (PMID: 14675609). Additionally, an mouse model with overexpression of *PRPH* (PMID: 15132161) showed massive and selective degeneration of motor axons during aging. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

amyotrophic lateral sclerosis type 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007103

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRPH variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 66

not providedTotal: 38

Amyotrophic lateral sclerosis type 1Total: 9

PRPH-related disorderTotal: 7

not specifiedTotal: 5

Amyotrophic lateral sclerosis, susceptibility toTotal: 2

Amyotrophic lateral sclerosisTotal: 2

Amyotrophic lateral sclerosis type 10Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006262.4. 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			2 clinvar	5 clinvar		7
missense			83 clinvar	3 clinvar	3 clinvar	89
nonsense		2 clinvar	3 clinvar			5
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		2 clinvar		1 clinvar		3
Total	0	4	90	9	3	106

Highest pathogenic variant AF is 0.000011152168

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006262.4	RefSeq	NP_006253.2	9	MANE Select
ENST00000257860.9	Ensembl	ENSP00000257860.4	9	MANE Select
ENST00000451891.4	Ensembl	ENSP00000408897.4	6	Standard
ENST00000532332.2	Ensembl	ENSP00000437182.2	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
Amyotrophic lateral sclerosis (ALS)

Molecular Function

structural molecule activity
protein binding

Cellular Component

intermediate filament
membrane
type III intermediate filament
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257860
Coding exons: 9
Length: 5431
Individuals with no LoFs: 124482
Homozygous LoFs: 6
Heterozygous LoFs: 1260
Defined: 125748
p: 0.00505

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.556	245	271	0.905	0.0000141	2987
Missense (PolyPhen)		98	102.02	0.96057		1111
Synonymous	0.163	121	123	0.981	0.00000620	965
Loss of Function	0.171	21	21.9	0.961	0.00000100	241

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00075	0.00074	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00099	0.00098	rare
Finnish	0.022	0.022	notable
European (Non-Finnish)	0.0063	0.0063	notable
South Asian	0.00077	0.00075	rare
Other	0.0026	0.0026	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Class-III neuronal intermediate filament protein.;

Recessive Scores

pRec: 0.412

Intolerance Scores

LoFtool: 0.394
RVIS EVS: 0.02
RVIS percentile EVS: 55.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.769

Gene Damage Prediction

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