KPNA3

protein-coding

karyopherin subunit alpha 3, the group of Armadillo repeat containing|Importins

Gene summary

The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. [provided by RefSeq, Jan 2009]

MANE transcript

NM_002267.4

Inheritance

ClinVar variants

P:6U:62B:4

Top phenotype

Spastic paraplegia 88, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr13:49,699,320-49,792,682

External References & Databases

Ensembl (ENSG00000102753)

Transcript & Mutation Effects

hg38 • Region Span ~93.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic paraplegia 88, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859309

Submitter: Ambry Genetics

spastic paraplegia 88, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859309

Submitter: Labcorp Genetics (formerly Invitae)

spastic paraplegia 88, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859309

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spastic paraplegia 88, autosomal dominantAD

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: 34564892; 34825409; 34981581

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KPNA3 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 35

not providedTotal: 19

Spastic paraplegia 88, autosomal dominantTotal: 11

not specifiedTotal: 2

KPNA3-related conditionTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002267.4. 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	1 clinvar		3
missense	4 clinvar	2 clinvar	51 clinvar	2 clinvar	1 clinvar	60
nonsense						0
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	2	62	3	1	72

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002267.4	RefSeq	NP_002258.2	17	MANE Select
ENST00000261667.8	Ensembl	ENSP00000261667.3	17	MANE Select
ENST00000436760.1	Ensembl	ENSP00000393869.1	4	Standard
ENST00000912490.1	Ensembl	ENSP00000582549.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Disease
NS1 Mediated Effects on Host Pathways
Host Interactions with Influenza Factors

Biological Process

NLS-bearing protein import into nucleus
modulation by virus of host process
viral entry into host cell
protein-containing complex assembly
viral penetration into host nucleus

Molecular Function

protein binding
protein C-terminus binding
nuclear localization sequence binding
protein transporter activity
nuclear import signal receptor activity

Cellular Component

nuclear pore
nucleoplasm
cytosol
host cell

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261667
Coding exons: 17
Length: 93611
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125738
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.39	110	266	0.414	0.0000125	3421
Missense (PolyPhen)		25	116.03	0.21547		1511
Synonymous	-0.585	98	90.9	1.08	0.00000444	973
Loss of Function	4.39	5	31.7	0.158	0.00000152	391

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran- dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non- classical NLS. Recognizes NLSs of influenza A virus nucleoprotein probably through ARM repeats 7-9.;

Recessive Scores

pRec: 0.224

Intolerance Scores

LoFtool: 0.476
RVIS EVS: -0.12
RVIS percentile EVS: 44.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.831

Gene Damage Prediction

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