12-30630927-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006390.4(IPO8):c.3047G>T(p.Gly1016Val) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,613,536 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.78

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012223065).

BP6

Variant 12-30630927-C-A is Benign according to our data. Variant chr12-30630927-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 712730.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000131 (20/152232) while in subpopulation AMR AF = 0.00124 (19/15294). AF 95% confidence interval is 0.000813. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4 link	c.3047G>T	p.Gly1016Val	missense_variant	Exon 25 of 25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 link	c.2432G>T	p.Gly811Val	missense_variant	Exon 21 of 21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 link	c.2996G>T	p.Gly999Val	missense_variant	Exon 25 of 25		XP_016874180.1
IPO8	XM_017018692.2 link	c.2861G>T	p.Gly954Val	missense_variant	Exon 24 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9 link	c.3047G>T	p.Gly1016Val	missense_variant	Exon 25 of 25	1	NM_006390.4	ENSP00000256079.4		O15397-1
IPO8	ENST00000544829.5 link	c.2432G>T	p.Gly811Val	missense_variant	Exon 21 of 21	2		ENSP00000444520.1		O15397-2

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000629

AC:

158

AN:

251136

AF XY:

0.000398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1461304

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00396

AC:

177

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5398

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111936

Other (OTH)

AF:

0.0000497

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41522

American (AMR)

AF:

0.00124

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000412

Hom.:

Bravo

AF:

0.000276

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 21, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

3.8

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;.

Vest4

0.49

MVP

0.46

MPC

1.0

ClinPred

0.14

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.65

Mutation Taster

=87/13

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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12-30630927-C-A

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