12-30634160-G-A

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.2822C>T(p.Ala941Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,613,838 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A941A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.73

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=0.1432952).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000598 (91/152124) while in subpopulation AMR AF= 0.00118 (18/15268). AF 95% confidence interval is 0.000762. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.2822C>T	p.Ala941Val	missense_variant	23/25	ENST00000256079.9
IPO8	NM_001190995.2	c.2207C>T	p.Ala736Val	missense_variant	19/21
IPO8	XM_017018691.3	c.2771C>T	p.Ala924Val	missense_variant	23/25
IPO8	XM_017018692.2	c.2636C>T	p.Ala879Val	missense_variant	22/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO8	ENST00000256079.9	c.2822C>T	p.Ala941Val	missense_variant	23/25	1	NM_006390.4	P1
IPO8	ENST00000544829.5	c.2207C>T	p.Ala736Val	missense_variant	19/21	2
IPO8	ENST00000535598.1	c.296C>T	p.Ala99Val	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.000853

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251274 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000870 AC: 1272 AN: 1461714 Hom.: 0 Cov.: 31 AF XY: 0.000843 AC XY: 613 AN XY: 727148

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74322

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000696 Hom.: 0

Bravo AF: 0.000778

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.00109

EpiControl AF: 0.000889

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

Aug 10, 2021

The c.2822C>T (p.A941V) alteration is located in exon 23 (coding exon 23) of the IPO8 gene. This alteration results from a C to T substitution at nucleotide position 2822, causing the alanine (A) at amino acid position 941 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.19
Sift	Benign	0.10	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.97	D;.
Vest4		0.37
MVP		0.48
MPC		0.29
ClinPred		0.15	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.22
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs150350956; hg19: chr12-30787094;