12-30637026-C-T

Position:

chr12-30637026-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_006390.4(IPO8):c.2651G>A(p.Arg884Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0810

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0320729).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000125 (183/1461770) while in subpopulation MID AF= 0.000867 (5/5768). AF 95% confidence interval is 0.000341. There are 1 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IPO8	NM_006390.4 linkuse as main transcript	c.2651G>A	p.Arg884Gln	missense_variant	22/25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2 linkuse as main transcript	c.2036G>A	p.Arg679Gln	missense_variant	18/21		NP_001177924.1
IPO8	XM_017018691.3 linkuse as main transcript	c.2600G>A	p.Arg867Gln	missense_variant	22/25		XP_016874180.1
IPO8	XM_017018692.2 linkuse as main transcript	c.2465G>A	p.Arg822Gln	missense_variant	21/24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9 linkuse as main transcript	c.2651G>A	p.Arg884Gln	missense_variant	22/25	1	NM_006390.4	ENSP00000256079	P1	O15397-1
IPO8	ENST00000544829.5 linkuse as main transcript	c.2036G>A	p.Arg679Gln	missense_variant	18/21	2		ENSP00000444520		O15397-2
IPO8	ENST00000535598.1 linkuse as main transcript	c.125G>A	p.Arg42Gln	missense_variant	1/3	3		ENSP00000446232

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

251102

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000904

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 18, 2023

The c.2651G>A (p.R884Q) alteration is located in exon 22 (coding exon 22) of the IPO8 gene. This alteration results from a G to A substitution at nucleotide position 2651, causing the arginine (R) at amino acid position 884 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

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.050

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.98

N;N

REVEL

Benign

0.059

Sift

Benign

0.33

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0020

B;.

Vest4

0.10

MVP

0.42

MPC

0.30

ClinPred

0.020

GERP RS

-0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

gMVP

0.054

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