13-20799320-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_022459.5(XPO4):​c.2167T>A​(p.Cys723Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

XPO4
NM_022459.5 missense

Scores

4
2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.76
Variant links:
Genes affected
XPO4 (HGNC:17796): (exportin 4) XPO4 belongs to a large family of karyopherins (see MIM 602738) that mediate the transport of proteins and other cargo between the nuclear and cytoplasmic compartments (Lipowsky et al., 2000 [PubMed 10944119]).[supplied by OMIM, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36145818).
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
XPO4NM_022459.5 linkuse as main transcriptc.2167T>A p.Cys723Ser missense_variant 16/23 ENST00000255305.11 NP_071904.4 Q9C0E2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
XPO4ENST00000255305.11 linkuse as main transcriptc.2167T>A p.Cys723Ser missense_variant 16/231 NM_022459.5 ENSP00000255305.6 Q9C0E2

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249218
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135220
show subpopulations
Gnomad AFR exome
AF:
0.000387
Gnomad AMR exome
AF:
0.00
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:
0.0000157
AC:
23
AN:
1461310
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
726942
show subpopulations
Gnomad4 AFR exome
AF:
0.000627
Gnomad4 AMR exome
AF:
0.00
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:
0.0000331
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152332
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000553
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000170
ESP6500AA
AF:
0.000541
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000331
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 20, 2024The c.2167T>A (p.C723S) alteration is located in exon 16 (coding exon 16) of the XPO4 gene. This alteration results from a T to A substitution at nucleotide position 2167, causing the cysteine (C) at amino acid position 723 to be replaced by a serine (S). 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
0.25
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
22
DANN
Benign
0.71
DEOGEN2
Benign
0.072
T;T
Eigen
Benign
-0.024
Eigen_PC
Benign
0.22
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.94
L;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.27
Sift
Benign
0.99
T;T
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.023
B;.
Vest4
0.89
MutPred
0.51
Gain of MoRF binding (P = 0.0563);Gain of MoRF binding (P = 0.0563);
MVP
0.45
MPC
0.96
ClinPred
0.21
T
GERP RS
5.7
Varity_R
0.43
gMVP
0.62

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200051725; hg19: chr13-21373459; API