9-128522658-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_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 (★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius 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 id is 6462.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-128522658-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLE1	NM_001003722.2 link	c.433-10A>G		intron_variant	Intron 3 of 15	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.433-10A>G		intron_variant	Intron 3 of 15	1	NM_001003722.2	ENSP00000308622.5		Q53GS7-1

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

GnomAD3 exomes

AF:

0.000970

AC:

198

AN:

204174

Hom.:

AF XY:

0.00103

AC XY:

114

AN XY:

111086

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.00908

Gnomad4 NFE exome

AF:

0.0000122

Gnomad4 OTH exome

AF:

0.000175

GnomAD4 genome

AF:

0.000766

AC:

AN:

112254

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

53828

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.0000385

Gnomad4 OTH

AF:

0.00199

Alfa

AF:

0.0000522

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lethal congenital contracture syndrome 1

Pathogenic:2

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NG_012073.1(NM_001003722.1):c.433-10A>G in the GLE1 gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database. This variant has been observed in individuals affected with lethal congenital contracture syndrome (PMID: 18204449) and is a founder variant in the Finnish population (PMID: 16892327; 7770128). Experimental studies have shown that this intronic change leads to aberrant mRNA splicing, resulting in a GLE1 protein with defective oligomerization (PMID: 24243016). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PP4. -

Lethal arthrogryposis-anterior horn cell disease syndrome

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the GLE1 gene. It does not directly change the encoded amino acid sequence of the GLE1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with lethal congenital contracture syndrome (PMID: 7770128, 16892327, 18204449). It is commonly reported in individuals of Finnish ancestry (PMID: 7770128, 16892327, 18204449). This variant is also known as Fin(Major). ClinVar contains an entry for this variant (Variation ID: 6462). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GLE1 function (PMID: 24243016). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Lethal congenital contractural syndrome Finnish type

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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