13-49725420-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_002267.4(KPNA3):​c.465G>T​(p.Gln155His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KPNA3
NM_002267.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KPNA3. . Gene score misZ 3.3927 (greater than the threshold 3.09). Trascript score misZ 3.1846 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia 88, autosomal dominant.
BP4
Computational evidence support a benign effect (MetaRNN=0.22183886).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KPNA3NM_002267.4 linkuse as main transcriptc.465G>T p.Gln155His missense_variant 7/17 ENST00000261667.8
KPNA3XM_017020561.2 linkuse as main transcriptc.393G>T p.Gln131His missense_variant 7/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KPNA3ENST00000261667.8 linkuse as main transcriptc.465G>T p.Gln155His missense_variant 7/171 NM_002267.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spastic paraplegia 88, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T
Eigen
Benign
-0.11
Eigen_PC
Benign
0.050
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.22
T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.95
N
REVEL
Benign
0.096
Sift
Benign
0.076
T
Sift4G
Uncertain
0.046
D
Polyphen
0.0
B
Vest4
0.26
MutPred
0.46
Gain of catalytic residue at V154 (P = 0.0021);
MVP
0.63
MPC
0.93
ClinPred
0.77
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.21

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: chr13-50299556; API