5-62474450-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016338.5(IPO11):c.743A>G(p.Gln248Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000842 in 1,425,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: IPO11 NM_016338.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

Genes affected

IPO11 (HGNC:20628): (importin 11) Importins, including IPO11, are a members of the karyopherin/importin-beta family of transport receptors (see KPNB1; 602738) that mediate nucleocytoplasmic transport of protein and RNA cargoes (Plafker and Macara, 2000 [PubMed 11032817]).[supplied by OMIM, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPO11	NM_016338.5	c.743A>G	p.Gln248Arg	missense_variant	8/30	ENST00000325324.11
IPO11	NM_001134779.2	c.863A>G	p.Gln288Arg	missense_variant	8/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO11	ENST00000325324.11	c.743A>G	p.Gln248Arg	missense_variant	8/30	1	NM_016338.5	P1
IPO11	ENST00000409296.7	c.863A>G	p.Gln288Arg	missense_variant	8/30	2
IPO11	ENST00000507640.1	n.154A>G		non_coding_transcript_exon_variant	3/4	3
IPO11	ENST00000424533.5	c.743A>G	p.Gln248Arg	missense_variant, NMD_transcript_variant	8/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000842 AC: 12 AN: 1425046 Hom.: 0 Cov.: 26 AF XY: 0.00000423 AC XY: 3 AN XY: 709228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.863A>G (p.Q288R) alteration is located in exon 8 (coding exon 8) of the IPO11 gene. This alteration results from a A to G substitution at nucleotide position 863, causing the glutamine (Q) at amino acid position 288 to be replaced by an arginine (R). 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	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.041	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.28
Sift	Benign	0.49	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.43	B;P
Vest4		0.79
MutPred		0.33		Gain of helix (P = 0.027);.;
MVP		0.89
MPC		0.34
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.53

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: rs1201212243; hg19: chr5-61770277;