5-62487811-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016338.5(IPO11):c.1259A>G(p.Tyr420Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IPO11 NM_016338.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPO11	NM_016338.5	c.1259A>G	p.Tyr420Cys	missense_variant	13/30	ENST00000325324.11
IPO11	NM_001134779.2	c.1379A>G	p.Tyr460Cys	missense_variant	13/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO11	ENST00000325324.11	c.1259A>G	p.Tyr420Cys	missense_variant	13/30	1	NM_016338.5	P1
IPO11	ENST00000409296.7	c.1379A>G	p.Tyr460Cys	missense_variant	13/30	2
IPO11	ENST00000424533.5	c.1259A>G	p.Tyr420Cys	missense_variant, NMD_transcript_variant	13/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jun 06, 2023

The c.1379A>G (p.Y460C) alteration is located in exon 13 (coding exon 13) of the IPO11 gene. This alteration results from a A to G substitution at nucleotide position 1379, causing the tyrosine (Y) at amino acid position 460 to be replaced by a cysteine (C). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.53		Gain of catalytic residue at H418 (P = 0.1004);.;
MVP		0.57
MPC		0.78
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.59
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-61783638; COSMIC: COSV57582388; COSMIC: COSV57582388;