5-62483266-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016338.5(IPO11):c.994G>A(p.Ala332Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000982 in 1,425,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: IPO11 NM_016338.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21736482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPO11	NM_016338.5	c.994G>A	p.Ala332Thr	missense_variant	10/30	ENST00000325324.11
IPO11	NM_001134779.2	c.1114G>A	p.Ala372Thr	missense_variant	10/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO11	ENST00000325324.11	c.994G>A	p.Ala332Thr	missense_variant	10/30	1	NM_016338.5	P1
IPO11	ENST00000409296.7	c.1114G>A	p.Ala372Thr	missense_variant	10/30	2
IPO11	ENST00000507640.1	n.334G>A		non_coding_transcript_exon_variant	4/4	3
IPO11	ENST00000424533.5	c.994G>A	p.Ala332Thr	missense_variant, NMD_transcript_variant	10/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000435 AC: 1 AN: 229940 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125100

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000982 AC: 14 AN: 1425984 Hom.: 0 Cov.: 29 AF XY: 0.00000566 AC XY: 4 AN XY: 707334

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: 0.0000128

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

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

Dec 05, 2022

The c.1114G>A (p.A372T) alteration is located in exon 10 (coding exon 10) of the IPO11 gene. This alteration results from a G to A substitution at nucleotide position 1114, causing the alanine (A) at amino acid position 372 to be replaced by a threonine (T). 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	0.024	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Benign	0.91
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.094
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.12
Sift	Benign	0.75	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0070	B;B
Vest4		0.46
MutPred		0.36		Loss of catalytic residue at A332 (P = 0.0869);.;
MVP		0.65
MPC		0.19
ClinPred		0.34	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1433333895; hg19: chr5-61779093; COSMIC: COSV100320131;