rs2275260

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001003722.2(GLE1):c.727A>G(p.Ile243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,590 control chromosomes in the GnomAD database, including 47,049 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6241 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40808 hom. )

Consequence

GLE1
NM_001003722.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.81

Publications

35 publications found

Variant links:

Genes affected

GLE1 (HGNC:4315): (GLE1 RNA export mediator) This gene encodes a predicted 75-kDa polypeptide with high sequence and structure homology to yeast Gle1p, which is nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)+RNA export. Inhibition of human GLE1L by microinjection of antibodies against GLE1L in HeLa cells resulted in inhibition of poly(A)+RNA export. Immunoflourescence studies show that GLE1L is localized at the nuclear pore complexes. This localization suggests that GLE1L may act at a terminal step in the export of mature RNA messages to the cytoplasm. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GLE1 Gene-Disease associations (from GenCC):

lethal arthrogryposis-anterior horn cell disease syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
lethal congenital contracture syndrome 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

GLE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.893707E-4).

BP6

Variant 9-128523676-A-G is Benign according to our data. Variant chr9-128523676-A-G is described in ClinVar as [Benign]. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLE1	NM_001003722.2 link	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 16	ENST00000309971.9	NP_001003722.1	Q53GS7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLE1	ENST00000309971.9 link	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 16	1	NM_001003722.2	ENSP00000308622.5		Q53GS7-1

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41216

AN:

151816

Hom.:

6231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.466

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.245

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.267

AC:

67017

AN:

251016

AF XY:

0.264

show subpopulations

Gnomad AFR exome

AF:

0.388

Gnomad AMR exome

AF:

0.308

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.244

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.227

AC:

331476

AN:

1461656

Hom.:

40808

Cov.:

AF XY:

0.229

AC XY:

166274

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.388

AC:

12990

AN:

33478

American (AMR)

AF:

0.300

AC:

13420

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

4370

AN:

26136

East Asian (EAS)

AF:

0.478

AC:

18981

AN:

39700

South Asian (SAS)

AF:

0.315

AC:

27210

AN:

86248

European-Finnish (FIN)

AF:

0.236

AC:

12617

AN:

53406

Middle Eastern (MID)

AF:

0.256

AC:

1474

AN:

5758

European-Non Finnish (NFE)

AF:

0.203

AC:

225941

AN:

1111824

Other (OTH)

AF:

0.240

AC:

14473

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14866

29732

44597

59463

74329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8122

16244

24366

32488

40610

<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:

0.272

AC:

41257

AN:

151934

Hom.:

6241

Cov.:

AF XY:

0.276

AC XY:

20493

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.376

AC:

15594

AN:

41422

American (AMR)

AF:

0.257

AC:

3922

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

561

AN:

3468

East Asian (EAS)

AF:

0.466

AC:

2390

AN:

5128

South Asian (SAS)

AF:

0.341

AC:

1645

AN:

4820

European-Finnish (FIN)

AF:

0.253

AC:

2668

AN:

10546

Middle Eastern (MID)

AF:

0.247

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.202

AC:

13729

AN:

67982

Other (OTH)

AF:

0.255

AC:

539

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1445

2889

4334

5778

7223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.233

Hom.:

14981

Bravo

AF:

0.281

TwinsUK

AF:

0.197

AC:

731

ALSPAC

AF:

0.205

AC:

789

ESP6500AA

AF:

0.388

AC:

1711

ESP6500EA

AF:

0.201

AC:

1732

ExAC

AF:

0.267

AC:

32374

Asia WGS

AF:

0.424

AC:

1472

AN:

3478

EpiCase

AF:

0.202

EpiControl

AF:

0.205

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 23421748) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal arthrogryposis-anterior horn cell disease syndrome

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lethal congenital contracture syndrome 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal congenital contractural syndrome Finnish type

Benign:1

Nov 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.8

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0053

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.086

T;T

MetaRNN

Benign

0.00059

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.0

N;N

PhyloP100

1.8

PrimateAI

Benign

0.27

PROVEAN

Benign

0.53

N;N

REVEL

Benign

0.23

Sift

Benign

0.11

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0

B;B

Vest4

0.0050

MPC

0.18

ClinPred

0.0033

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.040

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over