chr12-30634161-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006390.4(IPO8):​c.2821G>A​(p.Ala941Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.33
Variant links:
Genes affected
IPO8 (HGNC:9853): (importin 8) The importin-alpha/beta complex and the GTPase Ran mediate nuclear import of proteins with a classical nuclear localization signal. The protein encoded by this gene is a member of a class of approximately 20 potential Ran targets that share a sequence motif related to the Ran-binding site of importin-beta. This protein binds to the nuclear pore complex and, along with RanGTP and RANBP1, inhibits the GAP stimulation of the Ran GTPase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22174755).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IPO8NM_006390.4 linkc.2821G>A p.Ala941Thr missense_variant Exon 23 of 25 ENST00000256079.9 NP_006381.2 O15397-1
IPO8NM_001190995.2 linkc.2206G>A p.Ala736Thr missense_variant Exon 19 of 21 NP_001177924.1 O15397-2
IPO8XM_017018691.3 linkc.2770G>A p.Ala924Thr missense_variant Exon 23 of 25 XP_016874180.1
IPO8XM_017018692.2 linkc.2635G>A p.Ala879Thr missense_variant Exon 22 of 24 XP_016874181.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IPO8ENST00000256079.9 linkc.2821G>A p.Ala941Thr missense_variant Exon 23 of 25 1 NM_006390.4 ENSP00000256079.4 O15397-1
IPO8ENST00000544829.5 linkc.2206G>A p.Ala736Thr missense_variant Exon 19 of 21 2 ENSP00000444520.1 O15397-2
IPO8ENST00000535598.1 linkc.292G>A p.Ala98Thr missense_variant Exon 2 of 3 3 ENSP00000446232.1 H0YH64

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251306
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461718
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.13
Sift
Benign
0.032
D;D
Sift4G
Uncertain
0.059
T;T
Polyphen
0.75
P;.
Vest4
0.37
MutPred
0.34
Gain of relative solvent accessibility (P = 0.0082);.;
MVP
0.46
MPC
0.33
ClinPred
0.35
T
GERP RS
4.3
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.17
gMVP
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749525802; hg19: chr12-30787095; COSMIC: COSV56243304; API