12-30631906-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_006390.4(IPO8):c.3005G>A(p.Arg1002Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000956 in 1,610,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1002W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.09

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]

IPO8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06458318).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000381 (58/152278) while in subpopulation AFR AF = 0.00135 (56/41552). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4 link	c.3005G>A	p.Arg1002Gln	missense_variant	Exon 24 of 25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 link	c.2390G>A	p.Arg797Gln	missense_variant	Exon 20 of 21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 link	c.2954G>A	p.Arg985Gln	missense_variant	Exon 24 of 25		XP_016874180.1
IPO8	XM_017018692.2 link	c.2819G>A	p.Arg940Gln	missense_variant	Exon 23 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IPO8	ENST00000256079.9 link	c.3005G>A	p.Arg1002Gln	missense_variant	Exon 24 of 25	1	NM_006390.4	ENSP00000256079.4	O15397-1
IPO8	ENST00000544829.5 link	c.2390G>A	p.Arg797Gln	missense_variant	Exon 20 of 21	2		ENSP00000444520.1	O15397-2
IPO8	ENST00000535598.1 link	c.476G>A	p.Arg159Gln	missense_variant	Exon 3 of 3	3		ENSP00000446232.1	H0YH64

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000921

AC:

AN:

249780

AF XY:

0.0000815

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1457922

Hom.:

Cov.:

AF XY:

0.0000634

AC XY:

AN XY:

725462

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

33386

American (AMR)

AF:

0.0000224

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39670

South Asian (SAS)

AF:

0.000139

AC:

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52948

Middle Eastern (MID)

AF:

0.000213

AC:

AN:

4702

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1110210

Other (OTH)

AF:

0.000116

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000381

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3005G>A (p.R1002Q) alteration is located in exon 24 (coding exon 24) of the IPO8 gene. This alteration results from a G to A substitution at nucleotide position 3005, causing the arginine (R) at amino acid position 1002 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

4.1

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.11

Sift

Benign

0.058

T;T

Sift4G

Benign

0.089

T;T

Polyphen

0.34

B;.

Vest4

0.51

MVP

0.44

MPC

0.32

ClinPred

0.063

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.52

Mutation Taster

=78/22

polymorphism

(source)

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

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12-30631906-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over