12-30634159-C-A

Variant names:

• chr12-30634159-C-A
• rs756381329
• NM_006390.4:c.2823G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_006390.4(IPO8):​c.2823G>T​(p.Ala941Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A941A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IPO8 NM_006390.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.048).
• BP7: Synonymous conserved (PhyloP=-0.042 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2823G>T	p.Ala941Ala	synonymous_variant	Exon 23 of 25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2208G>T	p.Ala736Ala	synonymous_variant	Exon 19 of 21		NP_001177924.1
IPO8	XM_017018691.3	c.2772G>T	p.Ala924Ala	synonymous_variant	Exon 23 of 25		XP_016874180.1
IPO8	XM_017018692.2	c.2637G>T	p.Ala879Ala	synonymous_variant	Exon 22 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2823G>T	p.Ala941Ala	synonymous_variant	Exon 23 of 25	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.2208G>T	p.Ala736Ala	synonymous_variant	Exon 19 of 21	2		ENSP00000444520.1
IPO8	ENST00000535598.1	c.294G>T	p.Ala98Ala	synonymous_variant	Exon 2 of 3	3		ENSP00000446232.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251316 AF XY: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	6.9
DANN	Benign	0.55
PhyloP100		-0.042
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs756381329; hg19: chr12-30787093;