12-30634159-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_006390.4(IPO8):​c.2823G>A​(p.Ala941Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: IPO8 NM_006390.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Benign. The variant received -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant 12-30634159-C-T is Benign according to our data. Variant chr12-30634159-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3054391.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000506 (74/1461720) while in subpopulation AMR AF = 0.0000671 (3/44718). AF 95% confidence interval is 0.0000452. There are 0 homozygotes in GnomAdExome4. There are 37 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2823G>A	p.Ala941Ala	synonymous_variant	Exon 23 of 25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2208G>A	p.Ala736Ala	synonymous_variant	Exon 19 of 21		NP_001177924.1
IPO8	XM_017018691.3	c.2772G>A	p.Ala924Ala	synonymous_variant	Exon 23 of 25		XP_016874180.1
IPO8	XM_017018692.2	c.2637G>A	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>A	p.Ala941Ala	synonymous_variant	Exon 23 of 25	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.2208G>A	p.Ala736Ala	synonymous_variant	Exon 19 of 21	2		ENSP00000444520.1
IPO8	ENST00000535598.1	c.294G>A	p.Ala98Ala	synonymous_variant	Exon 2 of 3	3		ENSP00000446232.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000796 AC: 20 AN: 251316 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111902

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IPO8-related disorder Benign:1

Jun 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	10
DANN	Benign	0.53
PhyloP100		-0.042
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV56239462;