12-30631990-G-T

Position:

• chr12-30631990-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The ENST00000256079.9(IPO8):​c.2921C>A​(p.Ala974Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,310 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: IPO8 ENST00000256079.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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=0.13620153).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000473 (69/1460030) while in subpopulation MID AF= 0.00177 (10/5640). AF 95% confidence interval is 0.000962. There are 0 homozygotes in gnomad4_exome. There are 39 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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	Protein	UniProt
IPO8	NM_006390.4	c.2921C>A	p.Ala974Asp	missense_variant	24/25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2306C>A	p.Ala769Asp	missense_variant	20/21		NP_001177924.1
IPO8	XM_017018691.3	c.2870C>A	p.Ala957Asp	missense_variant	24/25		XP_016874180.1
IPO8	XM_017018692.2	c.2735C>A	p.Ala912Asp	missense_variant	23/24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2921C>A	p.Ala974Asp	missense_variant	24/25	1	NM_006390.4	ENSP00000256079	P1
IPO8	ENST00000544829.5	c.2306C>A	p.Ala769Asp	missense_variant	20/21	2		ENSP00000444520
IPO8	ENST00000535598.1	c.395C>A	p.Ala132Asp	missense_variant	3/3	3		ENSP00000446232

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000920 AC: 23 AN: 249894 Hom.: 0 AF XY: 0.0000888 AC XY: 12 AN XY: 135062

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000473 AC: 69 AN: 1460030 Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 726346

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000575

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jun 05, 2023

The c.2921C>A (p.A974D) alteration is located in exon 24 (coding exon 24) of the IPO8 gene. This alteration results from a C to A substitution at nucleotide position 2921, causing the alanine (A) at amino acid position 974 to be replaced by an aspartic acid (D). 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	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.13
Sift	Benign	0.20	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.57	P;.
Vest4		0.28
MutPred		0.51		Gain of catalytic residue at A973 (P = 0.0466);.;
MVP		0.43
MPC		0.40
ClinPred		0.20	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.51

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: rs767601464; hg19: chr12-30784924;