1-43960978-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_014652.4(IPO13):c.2212A>G(p.Ile738Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: IPO13 NM_014652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

Genes affected

IPO13 (HGNC:16853): (importin 13) This gene encodes a member of the importin-beta family of nuclear transport proteins. The encoded protein mediates the import of specific cargo proteins from the cytoplasm to the nucleus and is dependent on the Ras-related nuclear protein-GTPase system. The encoded protein is also involved in nuclear export of the eukaryotic translation initiation factor 1A.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IPO13
• BP4: Computational evidence support a benign effect (MetaRNN=0.077564776).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPO13	NM_014652.4	c.2212A>G	p.Ile738Val	missense_variant	13/20	ENST00000372343.8
IPO13	XM_024451069.2	c.1309A>G	p.Ile437Val	missense_variant	12/19
IPO13	XM_024451070.2	c.1309A>G	p.Ile437Val	missense_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPO13	ENST00000372343.8	c.2212A>G	p.Ile738Val	missense_variant	13/20	1	NM_014652.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251362 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

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

Mar 21, 2022

The c.2212A>G (p.I738V) alteration is located in exon 13 (coding exon 13) of the IPO13 gene. This alteration results from a A to G substitution at nucleotide position 2212, causing the isoleucine (I) at amino acid position 738 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	0.076
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.078
Sift	Benign	0.53	T
Sift4G	Benign	0.20	T
Polyphen		0.0060	B
Vest4		0.29
MutPred		0.27		Gain of helix (P = 0.0696);
MVP		0.28
MPC		0.38
ClinPred		0.15	T
GERP RS		3.3
Varity_R		0.044
gMVP		0.11

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: rs747907628; hg19: chr1-44426650;