NM_001003722.2:c.727A>G

Variant names:

• chr9-128523676-A-G
• rs2275260
• NM_001003722.2:c.727A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.81
• Publications: 35 publications found

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

ACMG classification

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 CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar as Benign. Clinvar id is 198109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128523676-A-G is described in CliVar 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	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 16	ENST00000309971.9	NP_001003722.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41216 AN: 151816 Hom.: 6231 Cov.: 31

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

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.: 35 AF XY: 0.229 AC XY: 166274 AN XY: 727130

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

GnomAD4 genome AF: 0.272 AC: 41257 AN: 151934 Hom.: 6241 Cov.: 31 AF XY: 0.276 AC XY: 20493 AN XY: 74250

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: 72 AN: 292

European-Non Finnish (NFE) AF: 0.202 AC: 13729 AN: 67982

Other (OTH) AF: 0.255 AC: 539 AN: 2114

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

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

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. -

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	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.8
DANN	Benign	0.54
DEOGEN2	Benign	0.0053	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.086	T;T
MetaRNN	Benign	0.00059	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.0	N;N
PhyloP100		1.8
PrimateAI	Benign	0.27	T
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	T
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)

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

Other links and lift over

dbSNP: rs2275260; hg19: chr9-131285955; COSMIC: COSV59406898;