Genetic Variant NM_006390.4:c.2902G>T (chr12-30632009-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006390.4(IPO8):c.2902G>T(p.Val968Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V968M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.514

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

VISS syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

IPO8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12381965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4 link	c.2902G>T	p.Val968Leu	missense_variant, splice_region_variant	Exon 24 of 25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 link	c.2287G>T	p.Val763Leu	missense_variant, splice_region_variant	Exon 20 of 21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 link	c.2851G>T	p.Val951Leu	missense_variant, splice_region_variant	Exon 24 of 25		XP_016874180.1
IPO8	XM_017018692.2 link	c.2716G>T	p.Val906Leu	missense_variant, splice_region_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.2902G>T	p.Val968Leu	missense_variant, splice_region_variant	Exon 24 of 25	1	NM_006390.4	ENSP00000256079.4	O15397-1
IPO8	ENST00000544829.5 link	c.2287G>T	p.Val763Leu	missense_variant, splice_region_variant	Exon 20 of 21	2		ENSP00000444520.1	O15397-2
IPO8	ENST00000535598.1 link	c.373G>T	p.Val125Leu	missense_variant, splice_region_variant	Exon 3 of 3	3		ENSP00000446232.1	H0YH64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1456936

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109852

Other (OTH)

AF:

0.0000166

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.060

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;.

PhyloP100

0.51

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.35

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.25

MutPred

0.46

Loss of helix (P = 0.0376);.;

MVP

0.26

MPC

0.26

ClinPred

0.48

GERP RS

5.0

Varity_R

0.081

gMVP

0.27

Mutation Taster

=84/16

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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NM_006390.4:c.2902G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over