Genetic Variant IPO8:p.Leu866ProfsTer12 (chr12-30637075-GGAAAA-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_006390.4(IPO8):c.2597_2601delTTTTC(p.Leu866ProfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

IPO8
NM_006390.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.96

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 was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-30637075-GGAAAA-G is Pathogenic according to our data. Variant chr12-30637075-GGAAAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1047912.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4 link	c.2597_2601delTTTTC	p.Leu866ProfsTer12	frameshift_variant	Exon 22 of 25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 link	c.1982_1986delTTTTC	p.Leu661ProfsTer12	frameshift_variant	Exon 18 of 21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 link	c.2546_2550delTTTTC	p.Leu849ProfsTer12	frameshift_variant	Exon 22 of 25		XP_016874180.1
IPO8	XM_017018692.2 link	c.2411_2415delTTTTC	p.Leu804ProfsTer12	frameshift_variant	Exon 21 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IPO8	ENST00000256079.9 link	c.2597_2601delTTTTC	p.Leu866ProfsTer12	frameshift_variant	Exon 22 of 25	1	NM_006390.4	ENSP00000256079.4	O15397-1
IPO8	ENST00000544829.5 link	c.1982_1986delTTTTC	p.Leu661ProfsTer12	frameshift_variant	Exon 18 of 21	2		ENSP00000444520.1	O15397-2
IPO8	ENST00000535598.1 link	c.68_72delTTTTC	p.Leu23fs	frameshift_variant	Exon 1 of 3	3		ENSP00000446232.1	H0YH64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250920

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461794

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111952

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

VISS syndrome

Pathogenic:1

Aug 05, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

IPO8-related aortopathy

Pathogenic:1

Mar 18, 2021

Centre of Medical Genetics, University of Antwerp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.0

Mutation Taster

=1/199

disease causing (fs/PTC)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr12-30637075-GGAAAA-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over