12-30634160-G-A

Position:

chr12-30634160-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_006390.4(IPO8):c.2822C>T(p.Ala941Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,613,838 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 (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.73

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1432952).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000598 (91/152124) while in subpopulation AMR AF= 0.00118 (18/15268). AF 95% confidence interval is 0.000762. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.2822C>T	p.Ala941Val	missense_variant	23/25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2 linkuse as main transcript	c.2207C>T	p.Ala736Val	missense_variant	19/21		NP_001177924.1
IPO8	XM_017018691.3 linkuse as main transcript	c.2771C>T	p.Ala924Val	missense_variant	23/25		XP_016874180.1
IPO8	XM_017018692.2 linkuse as main transcript	c.2636C>T	p.Ala879Val	missense_variant	22/24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9 linkuse as main transcript	c.2822C>T	p.Ala941Val	missense_variant	23/25	1	NM_006390.4	ENSP00000256079	P1	O15397-1
IPO8	ENST00000544829.5 linkuse as main transcript	c.2207C>T	p.Ala736Val	missense_variant	19/21	2		ENSP00000444520		O15397-2
IPO8	ENST00000535598.1 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant	2/3	3		ENSP00000446232

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000853

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000362

AC:

AN:

251274

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000870

AC:

1272

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000843

AC XY:

613

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00107

Gnomad4 OTH exome

AF:

0.000960

GnomAD4 genome

AF:

0.000598

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000696

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000889

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

Aug 10, 2021

The c.2822C>T (p.A941V) alteration is located in exon 23 (coding exon 23) of the IPO8 gene. This alteration results from a C to T substitution at nucleotide position 2822, causing the alanine (A) at amino acid position 941 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.19

Sift

Benign

0.10

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.97

D;.

Vest4

0.37

MVP

0.48

MPC

0.29

ClinPred

0.15

GERP RS

5.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.22

gMVP

0.15

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