Genetic Variant XPO1:c.301+56G>A (chr2-61522555-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003400.4(XPO1):c.301+56G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,471,006 control chromosomes in the GnomAD database, including 275,530 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 0.61 ( 28070 hom., cov: 32)

Exomes 𝑓: 0.61 ( 247460 hom. )

Consequence

XPO1
NM_003400.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0950

Publications

25 publications found

Variant links:

Genes affected

XPO1 (HGNC:12825): (exportin 1) This cell-cycle-regulated gene encodes a protein that mediates leucine-rich nuclear export signal (NES)-dependent protein transport. The protein specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1. [provided by RefSeq, Jan 2015]

XPO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO1	NM_003400.4	MANE Select	c.301+56G>A		intron	N/A	NP_003391.1	O14980
	XPO1	NM_001410799.1		c.301+56G>A		intron	N/A	NP_001397728.1	A0A7I2V2Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XPO1	ENST00000401558.7	TSL:1 MANE Select	c.301+56G>A	intron	N/A	ENSP00000384863.2	O14980
XPO1	ENST00000406957.5	TSL:1	c.301+56G>A	intron	N/A	ENSP00000385559.1	O14980
XPO1	ENST00000404992.6	TSL:2	c.301+56G>A	intron	N/A	ENSP00000385942.2	O14980

Frequencies

GnomAD3 genomes

AF:

0.606

AC:

92164

AN:

151966

Hom.:

28052

Cov.:

show subpopulations

Gnomad AFR

AF:

0.595

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.674

Gnomad EAS

AF:

0.650

Gnomad SAS

AF:

0.612

Gnomad FIN

AF:

0.603

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.632

GnomAD4 exome

AF:

0.611

AC:

806052

AN:

1318922

Hom.:

247460

AF XY:

0.612

AC XY:

405425

AN XY:

662418

show subpopulations

African (AFR)

AF:

0.599

AC:

18000

AN:

30064

American (AMR)

AF:

0.575

AC:

24683

AN:

42918

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

17076

AN:

24904

East Asian (EAS)

AF:

0.659

AC:

25455

AN:

38604

South Asian (SAS)

AF:

0.608

AC:

49692

AN:

81716

European-Finnish (FIN)

AF:

0.601

AC:

31178

AN:

51844

Middle Eastern (MID)

AF:

0.703

AC:

3840

AN:

5464

European-Non Finnish (NFE)

AF:

0.609

AC:

601558

AN:

988058

Other (OTH)

AF:

0.625

AC:

34570

AN:

55350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

14721

29442

44163

58884

73605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15610

31220

46830

62440

78050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.606

AC:

92237

AN:

152084

Hom.:

28070

Cov.:

AF XY:

0.607

AC XY:

45133

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.595

AC:

24698

AN:

41498

American (AMR)

AF:

0.575

AC:

8776

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.674

AC:

2339

AN:

3470

East Asian (EAS)

AF:

0.650

AC:

3366

AN:

5180

South Asian (SAS)

AF:

0.612

AC:

2948

AN:

4820

European-Finnish (FIN)

AF:

0.603

AC:

6371

AN:

10560

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.612

AC:

41573

AN:

67972

Other (OTH)

AF:

0.632

AC:

1332

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1893

3786

5679

7572

9465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

774

1548

2322

3096

3870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.606

Hom.:

35201

Bravo

AF:

0.605

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

9.6

(source)

DANN

Benign

0.67

PhyloP100

0.095

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

2.9

Mutation Taster

=27/73

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over