Genetic Variant XPO1:p.Asn200Ile (chr2-61498905-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_003400.4(XPO1):c.599A>T(p.Asn200Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N200S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

XPO1
NM_003400.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.26

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 6.0107 (above the threshold of 3.09). Trascript score misZ: 7.9387 (above the threshold of 3.09).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.774

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.599A>T	p.Asn200Ile	missense	Exon 8 of 25	NP_003391.1	O14980
	XPO1	NM_001410799.1		c.599A>T	p.Asn200Ile	missense	Exon 8 of 24	NP_001397728.1	A0A7I2V2Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XPO1	ENST00000401558.7	TSL:1 MANE Select	c.599A>T	p.Asn200Ile	missense	Exon 8 of 25	ENSP00000384863.2	O14980
XPO1	ENST00000406957.5	TSL:1	c.599A>T	p.Asn200Ile	missense	Exon 9 of 26	ENSP00000385559.1	O14980
XPO1	ENST00000404992.6	TSL:2	c.599A>T	p.Asn200Ile	missense	Exon 8 of 25	ENSP00000385942.2	O14980

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1434772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712534

African (AFR)

AF:

0.00

AC:

AN:

31938

American (AMR)

AF:

0.00

AC:

AN:

39106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

39376

South Asian (SAS)

AF:

0.00

AC:

AN:

80892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101302

Other (OTH)

AF:

0.00

AC:

AN:

59136

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

6.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.4

REVEL

Benign

0.22

Sift

Benign

0.030

Sift4G

Benign

0.064

Polyphen

0.67

Vest4

0.85

MutPred

0.54

Loss of disorder (P = 0.0444)

MVP

0.49

MPC

2.1

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.64

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over