chr13-49792439-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_002267.4(KPNA3):c.68A>C(p.Glu23Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000159 in 1,572,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
KPNA3
NM_002267.4 missense, splice_region
NM_002267.4 missense, splice_region
Scores
2
4
13
Splicing: ADA: 0.9939
2
Clinical Significance
Conservation
PhyloP100: 4.30
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 Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KPNA3
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS2
?
High AC in GnomAdExome at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KPNA3 | NM_002267.4 | c.68A>C | p.Glu23Ala | missense_variant, splice_region_variant | 1/17 | ENST00000261667.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KPNA3 | ENST00000261667.8 | c.68A>C | p.Glu23Ala | missense_variant, splice_region_variant | 1/17 | 1 | NM_002267.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000265 AC: 4AN: 150980Hom.: 0 Cov.: 31
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.0000276 AC: 6AN: 217294Hom.: 0 AF XY: 0.0000504 AC XY: 6AN XY: 119128
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GnomAD4 exome AF: 0.0000148 AC: 21AN: 1421964Hom.: 0 Cov.: 31 AF XY: 0.0000240 AC XY: 17AN XY: 707446
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GnomAD4 genome ? AF: 0.0000265 AC: 4AN: 150980Hom.: 0 Cov.: 31 AF XY: 0.0000407 AC XY: 3AN XY: 73694
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 01, 2023 | The c.68A>C (p.E23A) alteration is located in exon 1 (coding exon 1) of the KPNA3 gene. This alteration results from a A to C substitution at nucleotide position 68, causing the glutamic acid (E) at amino acid position 23 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at R26 (P = 0.0062);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at