Variant 16-28125830-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_015171.4(XPO6):c.1625C>T(p.Thr542Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,906 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

XPO6
NM_015171.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.75

Variant links:

Genes affected

XPO6 (HGNC:19733): (exportin 6) The protein encoded by this gene is a member of the importin-beta family. Members of this family are regulated by the GTPase Ran to mediate transport of cargo across the nuclear envelope. This protein has been shown to mediate nuclear export of profilin-actin complexes. A pseudogene of this gene is located on the long arm of chromosome 14. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

XPO6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, XPO6

BP4

Computational evidence support a benign effect (MetaRNN=0.024399698).

BS2

High AC in GnomAd at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPO6	NM_015171.4 linkuse as main transcript	c.1625C>T	p.Thr542Met	missense_variant	13/24	ENST00000304658.10
XPO6	NM_001270940.2 linkuse as main transcript	c.1583C>T	p.Thr528Met	missense_variant	14/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPO6	ENST00000304658.10 linkuse as main transcript	c.1625C>T	p.Thr542Met	missense_variant	13/24	1	NM_015171.4	P1	Q96QU8-1

Frequencies

GnomAD3 genomes

AF:

0.000801

AC:

122

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000838

AC:

208

AN:

248258

Hom.:

AF XY:

0.000771

AC XY:

104

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.000957

Gnomad ASJ exome

AF:

0.00589

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000915

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.00113

AC:

1650

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

785

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152358

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000497

AC:

ESP6500EA

AF:

0.00191

AC:

ExAC

AF:

0.000612

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00119

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 submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.1625C>T (p.T542M) alteration is located in exon 13 (coding exon 13) of the XPO6 gene. This alteration results from a C to T substitution at nucleotide position 1625, causing the threonine (T) at amino acid position 542 to be replaced by a methionine (M). 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

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.5

N;N

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

.;D

Vest4

0.71

MVP

0.068

MPC

0.72

ClinPred

0.043

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over