12-30647419-T-C

Variant names:

• chr12-30647419-T-C
• rs3910564
• NM_006390.4:c.2268+1718A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006390.4(IPO8):​c.2268+1718A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,462 control chromosomes in the GnomAD database, including 24,545 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24545 hom., cov: 28)
• Consequence: IPO8 NM_006390.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.66
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006390.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO8	NM_006390.4	MANE Select	c.2268+1718A>G		intron	N/A	NP_006381.2
	IPO8	NM_001190995.2		c.1653+1718A>G		intron	N/A	NP_001177924.1	O15397-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO8	ENST00000256079.9	TSL:1 MANE Select	c.2268+1718A>G		intron	N/A	ENSP00000256079.4	O15397-1
	IPO8	ENST00000910950.1		c.2364+1718A>G		intron	N/A	ENSP00000581009.1
	IPO8	ENST00000910953.1		c.2361+1718A>G		intron	N/A	ENSP00000581012.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84547 AN: 151344 Hom.: 24524 Cov.: 28

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.532

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.559 AC: 84596 AN: 151462 Hom.: 24545 Cov.: 28 AF XY: 0.554 AC XY: 40981 AN XY: 73960

African (AFR) AF: 0.711 AC: 29336 AN: 41280

American (AMR) AF: 0.384 AC: 5844 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1927 AN: 3468

East Asian (EAS) AF: 0.442 AC: 2268 AN: 5134

South Asian (SAS) AF: 0.411 AC: 1970 AN: 4794

European-Finnish (FIN) AF: 0.591 AC: 6155 AN: 10422

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35518 AN: 67838

Other (OTH) AF: 0.531 AC: 1119 AN: 2108

Alfa AF: 0.523 Hom.: 10565

Bravo AF: 0.547

Asia WGS AF: 0.422 AC: 1469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.062
DANN	Benign	0.29
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3910564;

hg19: chr12-30800353;