SERPINI1

protein-coding

serpin family I member 1, the group of Serpin peptidase inhibitors

Gene summary

This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The protein is primarily secreted by axons in the brain, and preferentially reacts with and inhibits tissue-type plasminogen activator. It is thought to play a role in the regulation of axonal growth and the development of synaptic plasticity. Mutations in this gene result in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is a dominantly inherited form of familial encephalopathy and epilepsy characterized by the accumulation of mutant neuroserpin polymers. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

Previous symbols:

PI12

MANE transcript

NM_001122752.2

Inheritance

ClinVar variants

P:6U:219B:96

Top phenotype

Encephalopathy, familial, with neuroserpin inclusion bodies

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr3:167,735,243-167,825,569

External References & Databases

Ensembl (ENSG00000163536)

Transcript & Mutation Effects

hg38 • Region Span ~90.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial encephalopathy with neuroserpin inclusion bodiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011412

Submitter: Labcorp Genetics (formerly Invitae)

familial encephalopathy with neuroserpin inclusion bodiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011412

Submitter: Ambry Genetics

progressive myoclonus epilepsyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020074

Submitter: ClinGen

SERPINI1 was first reported in relation to an autosomal dominant condition with progressive psychomotor deterioration and neuroserpin-immunoreactive inclusion body in a large family in 1999 (Davis et al. 1999 PMID: 10517635). The onset of this family was in their 40’s and epilepsy was not present. Later, this family was found to be on the milder spectrum of this condition, because families reported after this initial publication had earlier age of onset (7-30 yo) and epilepsy. Typical phenotypes of these probands were psychomotor deterioration, progressive myoclonus epilepsy, and Periodic Acid-Schiff-positive, diastase resistant, and neuroserpin-immunoreactive inclusion bodies called Collins bodies in the brain. For this reason, SERPINI1 is curated for autosomal dominant progressive myoclonus epilepsy. Seven missense SERPINI1 variants that have been reported in twelve probands in nine publications have been included in this curation. The mechanism of pathogenicity appears to be GOF. Of the twelve reported families, ten had variants with functional studies and/or neuroserpin-immuoreactive inclusion bodies in the brain and were awarded 0.5 pts. Five families received additional 0.5 pts, because the variants were de novo. Four variants were recurrent in nine families, and each received 0.5 pts more. For the large family studied in PMID: 10517635, LOD score of 3.4 was published, resulting in 1 pt for segregation. In total, maximum score for genetic evidence (12 pts) has been reached. There was no scorable experimental evidence for this gene-disease association. In summary, SERPINI1 is definitively associated with autosomal dominant progressive myoclonus epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

familial encephalopathy with neuroserpin inclusion bodiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011412

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Encephalopathy, familial, with neuroserpin inclusion bodiesAD

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: 10517635; 12103288

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINI1 variants in ClinVar

6 Conditions Cataloged

Familial encephalopathy with neuroserpin inclusion bodiesTotal: 351

Inborn genetic diseasesTotal: 44

not specifiedTotal: 34

not providedTotal: 31

SERPINI1-related disorderTotal: 15

Abnormality of the nervous systemTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001122752.2. 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			1 clinvar	74 clinvar		75
missense	5 clinvar	1 clinvar	205 clinvar	21 clinvar	1 clinvar	233
nonsense			3 clinvar			3
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	5	1	219	95	1	321

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001122752.2	RefSeq	NP_001116224.1	8	MANE Select
ENST00000446050.7	Ensembl	ENSP00000397373.2	8	MANE Select
NM_005025.5	RefSeq	NP_005016.1	8	Standard
ENST00000295777.10	Ensembl	ENSP00000295777.5	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Validated targets of C-MYC transcriptional activation

Biological Process

central nervous system development
peripheral nervous system development
negative regulation of endopeptidase activity
positive regulation of neuron projection development
regulation of cell adhesion

Molecular Function

serine-type endopeptidase inhibitor activity

Cellular Component

extracellular space
secretory granule lumen
neuronal cell body
perikaryon
cytoplasmic vesicle lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295777
Coding exons: 8
Length: 90326
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125744
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.419	194	211	0.919	0.00000968	2742
Missense (PolyPhen)		63	81.588	0.77217		1086
Synonymous	0.702	64	71.6	0.894	0.00000330	739
Loss of Function	2.68	6	18.4	0.326	8.72e-7	232

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin (PubMed:9442076, PubMed:26329378, PubMed:19265707, PubMed:19285087, PubMed:11880376). May be involved in the formation or reorganization of synaptic connections as well as for synaptic plasticity in the adult nervous system. May protect neurons from cell damage by tissue-type plasminogen activator (Probable). {ECO:0000269|PubMed:11880376, ECO:0000269|PubMed:19265707, ECO:0000269|PubMed:19285087, ECO:0000269|PubMed:26329378, ECO:0000269|PubMed:9442076, ECO:0000305}.;

Recessive Scores

pRec: 0.232

Intolerance Scores

LoFtool: 0.0614
RVIS EVS: 1.15
RVIS percentile EVS: 92.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

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