12-30631907-G-A

Variant names:

• chr12-30631907-G-A
• rs151232989
• NM_006390.4:c.3004C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_006390.4(IPO8):​c.3004C>T​(p.Arg1002Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,610,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.939

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000177 (27/152160) while in subpopulation AFR AF= 0.000579 (24/41426). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.3004C>T	p.Arg1002Trp	missense_variant	Exon 24 of 25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2389C>T	p.Arg797Trp	missense_variant	Exon 20 of 21		NP_001177924.1
IPO8	XM_017018691.3	c.2953C>T	p.Arg985Trp	missense_variant	Exon 24 of 25		XP_016874180.1
IPO8	XM_017018692.2	c.2818C>T	p.Arg940Trp	missense_variant	Exon 23 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.3004C>T	p.Arg1002Trp	missense_variant	Exon 24 of 25	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.2389C>T	p.Arg797Trp	missense_variant	Exon 20 of 21	2		ENSP00000444520.1
IPO8	ENST00000535598.1	c.475C>T	p.Arg159Trp	missense_variant	Exon 3 of 3	3		ENSP00000446232.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249900 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135064

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1458466 Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15 AN XY: 725664

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74338

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3004C>T (p.R1002W) alteration is located in exon 24 (coding exon 24) of the IPO8 gene. This alteration results from a C to T substitution at nucleotide position 3004, causing the arginine (R) at amino acid position 1002 to be replaced by a tryptophan (W). 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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	0.040
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.71
MVP		0.63
MPC		0.68
ClinPred		0.87	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs151232989; hg19: chr12-30784841; COSMIC: COSV56244177;