rs626716

Variant names:

• chr13-97992999-A-G
• rs626716
• NM_002271.6:c.777A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP7 BA1

The NM_002271.6(IPO5):​c.777A>G​(p.Leu259Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 1,613,432 control chromosomes in the GnomAD database, including 4,914 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (694 hom., cov: 33)
  • Exomes 𝑓: 0.056 (4220 hom.)
• Consequence: IPO5 NM_002271.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• Publications: 16 publications found

Genes affected

IPO5 (HGNC:6402): (importin 5) Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.283).
• BP7: Synonymous conserved (PhyloP=0.275 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002271.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO5	NM_002271.6	MANE Select	c.777A>G	p.Leu259Leu	synonymous	Exon 10 of 29	NP_002262.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO5	ENST00000651721.2	MANE Select	c.777A>G	p.Leu259Leu	synonymous	Exon 10 of 29	ENSP00000499125.1
	IPO5	ENST00000261574.10	TSL:1	c.831A>G	p.Leu277Leu	synonymous	Exon 10 of 29	ENSP00000261574.5
	IPO5	ENST00000490680.5	TSL:1	c.777A>G	p.Leu259Leu	synonymous	Exon 7 of 26	ENSP00000418393.1

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11414 AN: 152112 Hom.: 693 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0790 AC: 19842 AN: 251272 AF XY: 0.0803

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0632

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0665

GnomAD4 exome AF: 0.0556 AC: 81254 AN: 1461202 Hom.: 4220 Cov.: 32 AF XY: 0.0580 AC XY: 42129 AN XY: 726812

African (AFR) AF: 0.113 AC: 3765 AN: 33460

American (AMR) AF: 0.0309 AC: 1380 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 1634 AN: 26126

East Asian (EAS) AF: 0.287 AC: 11380 AN: 39666

South Asian (SAS) AF: 0.138 AC: 11881 AN: 86182

European-Finnish (FIN) AF: 0.0432 AC: 2308 AN: 53416

Middle Eastern (MID) AF: 0.0674 AC: 389 AN: 5768

European-Non Finnish (NFE) AF: 0.0397 AC: 44140 AN: 1111514

Other (OTH) AF: 0.0725 AC: 4377 AN: 60358

GnomAD4 genome AF: 0.0751 AC: 11427 AN: 152230 Hom.: 694 Cov.: 33 AF XY: 0.0772 AC XY: 5744 AN XY: 74436

African (AFR) AF: 0.111 AC: 4590 AN: 41520

American (AMR) AF: 0.0465 AC: 711 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3468

East Asian (EAS) AF: 0.331 AC: 1716 AN: 5180

South Asian (SAS) AF: 0.161 AC: 775 AN: 4822

European-Finnish (FIN) AF: 0.0415 AC: 440 AN: 10604

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0394 AC: 2683 AN: 68024

Other (OTH) AF: 0.0715 AC: 151 AN: 2112

Alfa AF: 0.0539 Hom.: 1052

Bravo AF: 0.0774

Asia WGS AF: 0.232 AC: 804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.4
DANN	Benign	0.73
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs626716; hg19: chr13-98645253; COSMIC: COSV55154921; COSMIC: COSV55154921;