chr12-30631906-C-T

Position:

chr12-30631906-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IPO8	NM_006390.4 linkuse as main transcript	c.3005G>A	p.Arg1002Gln	missense_variant	24/25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 linkuse as main transcript	c.2390G>A	p.Arg797Gln	missense_variant	20/21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 linkuse as main transcript	c.2954G>A	p.Arg985Gln	missense_variant	24/25		XP_016874180.1
IPO8	XM_017018692.2 linkuse as main transcript	c.2819G>A	p.Arg940Gln	missense_variant	23/24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IPO8	ENST00000256079.9 linkuse as main transcript	c.3005G>A	p.Arg1002Gln	missense_variant	24/25	1	NM_006390.4	ENSP00000256079.4	O15397-1
IPO8	ENST00000544829.5 linkuse as main transcript	c.2390G>A	p.Arg797Gln	missense_variant	20/21	2		ENSP00000444520.1	O15397-2
IPO8	ENST00000535598.1 linkuse as main transcript	c.476G>A	p.Arg159Gln	missense_variant	3/3	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

GnomAD3 exomes

AF:

0.0000921

AC:

AN:

249780

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

135014

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 SAS exome

AF:

0.000164

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

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000381

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000881

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

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

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;.

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over