9-128522658-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3PP3PP5_Moderate

The NM_001003722.2(GLE1):c.433-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,498,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001142404: Experimental studies have shown that this intronic change leads to aberrant mRNA splicing, resulting in a GLE1 protein with defective oligomerization (PMID:24243016)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

GLE1
NM_001003722.2 intron

Scores

Splicing: ADA: 0.9987

Clinical Significance

Pathogenic criteria provided, single submitter P:5

Conservation

PhyloP100: 0.0570

Publications

5 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: G2P, Orphanet
lethal congenital contracture syndrome 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001142404: Experimental studies have shown that this intronic change leads to aberrant mRNA splicing, resulting in a GLE1 protein with defective oligomerization (PMID: 24243016).; SCV000965128: Experimental studies have shown that this variant affects GLE1 function (PMID: 24243016).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-128522658-A-G is Pathogenic according to our data. Variant chr9-128522658-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6462.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003722.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLE1	NM_001003722.2	MANE Select	c.433-10A>G	intron	N/A	NP_001003722.1	Q53GS7-1
GLE1	NM_001411013.1		c.433-10A>G	intron	N/A	NP_001397942.1	A0A804HJ70
GLE1	NM_001499.2		c.433-10A>G	intron	N/A	NP_001490.1	B3KMG0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLE1	ENST00000309971.9	TSL:1 MANE Select	c.433-10A>G	intron	N/A	ENSP00000308622.5	Q53GS7-1
GLE1	ENST00000372770.4	TSL:1	c.433-10A>G	intron	N/A	ENSP00000361856.4	Q53GS7-2
GLE1	ENST00000898507.1		c.433-10A>G	intron	N/A	ENSP00000568566.1

Frequencies

GnomAD3 genomes

AF:

0.000767

AC:

AN:

112182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0125

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000385

Gnomad OTH

AF:

0.00201

GnomAD2 exomes

AF:

0.000970

AC:

198

AN:

204174

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.000328

AC:

455

AN:

1385890

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

217

AN XY:

689252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30796

American (AMR)

AF:

0.00

AC:

AN:

37458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24596

East Asian (EAS)

AF:

0.00

AC:

AN:

37948

South Asian (SAS)

AF:

0.0000374

AC:

AN:

80192

European-Finnish (FIN)

AF:

0.00908

AC:

429

AN:

47256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4658

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

1065812

Other (OTH)

AF:

0.000175

AC:

AN:

57174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000766

AC:

AN:

112254

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

53828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30342

American (AMR)

AF:

0.00

AC:

AN:

11176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2664

East Asian (EAS)

AF:

0.00

AC:

AN:

3806

South Asian (SAS)

AF:

0.00

AC:

AN:

3418

European-Finnish (FIN)

AF:

0.0125

AC:

AN:

6504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000385

AC:

AN:

51898

Other (OTH)

AF:

0.00199

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000296

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lethal congenital contracture syndrome 1 (2)

Lethal arthrogryposis-anterior horn cell disease syndrome (1)

Lethal congenital contractural syndrome Finnish type (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.057

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.54

Position offset: 1

DS_AL_spliceai

0.52

Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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