rs1566333261

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_002267.4(KPNA3):​c.1006T>C​(p.Ser336Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S336T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

KPNA3
NM_002267.4 missense

Scores

2
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.46
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 3 ACMG points.

PM1
In a repeat ARM 7 (size 41) in uniprot entity IMA4_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002267.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3432812).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KPNA3NM_002267.4 linkc.1006T>C p.Ser336Pro missense_variant Exon 12 of 17 ENST00000261667.8 NP_002258.2 O00505A0A024RDV7
KPNA3XM_017020561.2 linkc.934T>C p.Ser312Pro missense_variant Exon 12 of 17 XP_016876050.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KPNA3ENST00000261667.8 linkc.1006T>C p.Ser336Pro missense_variant Exon 12 of 17 1 NM_002267.4 ENSP00000261667.3 O00505

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461476
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727080
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.18
Sift
Benign
0.040
D
Sift4G
Benign
0.078
T
Polyphen
0.16
B
Vest4
0.44
MutPred
0.52
Gain of catalytic residue at L335 (P = 0.0139);
MVP
0.57
MPC
1.4
ClinPred
0.98
D
GERP RS
3.9
Varity_R
0.34
gMVP
0.71

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: chr13-50283734; API