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13-49709621-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_ModeratePP5

The NM_002267.4(KPNA3):c.983T>C(p.Leu328Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L328M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KPNA3
NM_002267.4 missense

Scores

10
8
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.25
Variant links:
Genes affected
KPNA3 (HGNC:6396): (karyopherin subunit alpha 3) 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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1
?
    PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Transcript NM_002267.4 (KPNA3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a region_of_interest NLS binding site (minor) (size 88) in uniprot entity IMA4_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_002267.4
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, KPNA3
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.883
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 13-49709621-A-G is Pathogenic according to our data. Variant chr13-49709621-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1713275.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KPNA3NM_002267.4 linkuse as main transcriptc.983T>C p.Leu328Pro missense_variant 12/17 ENST00000261667.8
KPNA3XM_017020561.2 linkuse as main transcriptc.911T>C p.Leu304Pro missense_variant 12/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KPNA3ENST00000261667.8 linkuse as main transcriptc.983T>C p.Leu328Pro missense_variant 12/171 NM_002267.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Spastic paraplegia 88, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 02, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
Cadd
Pathogenic
31
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Pathogenic
4.0
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.78
P
Vest4
0.96
MutPred
0.66
Gain of catalytic residue at V327 (P = 0.0084);
MVP
0.91
MPC
1.6
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-50283757; COSMIC: COSV55507131; COSMIC: COSV55507131; API