12-30637027-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_006390.4(IPO8):c.2650C>G(p.Arg884Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R884Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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 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=0.100014806).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000363 (53/1461774) while in subpopulation NFE AF= 0.0000468 (52/1111922). AF 95% confidence interval is 0.0000363. There are 0 homozygotes in gnomad4_exome. There are 22 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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	UniProt
IPO8	NM_006390.4	c.2650C>G	p.Arg884Gly	missense_variant	22/25	ENST00000256079.9
IPO8	NM_001190995.2	c.2035C>G	p.Arg679Gly	missense_variant	18/21
IPO8	XM_017018691.3	c.2599C>G	p.Arg867Gly	missense_variant	22/25
IPO8	XM_017018692.2	c.2464C>G	p.Arg822Gly	missense_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO8	ENST00000256079.9	c.2650C>G	p.Arg884Gly	missense_variant	22/25	1	NM_006390.4	P1
IPO8	ENST00000544829.5	c.2035C>G	p.Arg679Gly	missense_variant	18/21	2
IPO8	ENST00000535598.1	c.124C>G	p.Arg42Gly	missense_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251102 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135724

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74226

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2022

The c.2650C>G (p.R884G) alteration is located in exon 22 (coding exon 22) of the IPO8 gene. This alteration results from a C to G substitution at nucleotide position 2650, causing the arginine (R) at amino acid position 884 to be replaced by a glycine (G). 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	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Benign	0.44
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.24	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0060	B;.
Vest4		0.22
MutPred		0.46		Loss of MoRF binding (P = 0.0421);.;
MVP		0.47
MPC		0.34
ClinPred		0.030	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376809979; hg19: chr12-30789961;