12-30637041-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006390.4(IPO8):c.2636G>A(p.Arg879Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,952 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (125 hom.)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.85

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042545497).
• BP6: Variant 12-30637041-C-T is Benign according to our data. Variant chr12-30637041-C-T is described in ClinVar as [Benign]. Clinvar id is 1701194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00759 (1156/152226) while in subpopulation NFE AF= 0.0126 (860/68020). AF 95% confidence interval is 0.0119. There are 4 homozygotes in gnomad4. There are 524 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPO8	NM_006390.4	c.2636G>A	p.Arg879Lys	missense_variant	22/25	ENST00000256079.9
IPO8	NM_001190995.2	c.2021G>A	p.Arg674Lys	missense_variant	18/21
IPO8	XM_017018691.3	c.2585G>A	p.Arg862Lys	missense_variant	22/25
IPO8	XM_017018692.2	c.2450G>A	p.Arg817Lys	missense_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO8	ENST00000256079.9	c.2636G>A	p.Arg879Lys	missense_variant	22/25	1	NM_006390.4	P1
IPO8	ENST00000544829.5	c.2021G>A	p.Arg674Lys	missense_variant	18/21	2
IPO8	ENST00000535598.1	c.110G>A	p.Arg37Lys	missense_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1155 AN: 152108 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00831 AC: 2087 AN: 251102 Hom.: 16 AF XY: 0.00861 AC XY: 1168 AN XY: 135706

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00689

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.0118 AC: 17232 AN: 1461726 Hom.: 125 Cov.: 32 AF XY: 0.0117 AC XY: 8494 AN XY: 727152

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00678

Gnomad4 FIN exome AF: 0.00468

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.00759 AC: 1156 AN: 152226 Hom.: 4 Cov.: 32 AF XY: 0.00704 AC XY: 524 AN XY: 74430

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0118 Hom.: 24

Bravo AF: 0.00773

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00864 AC: 1049

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

IPO8: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.87
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.11
Sift	Benign	0.31	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.10	B;.
Vest4		0.22
MVP		0.42
MPC		0.27
ClinPred		0.019	T
GERP RS		3.2
Varity_R		0.071
gMVP		0.33

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

Other links and lift over

dbSNP: rs61751231; hg19: chr12-30789975;