rs2275260

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: Orphanet, ClinGen

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 ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLE1	NM_001003722.2	MANE Select	c.727A>G	p.Ile243Val	missense	Exon 6 of 16	NP_001003722.1	Q53GS7-1
	GLE1	NM_001411013.1		c.727A>G	p.Ile243Val	missense	Exon 6 of 17	NP_001397942.1	A0A804HJ70
	GLE1	NM_001499.2		c.727A>G	p.Ile243Val	missense	Exon 6 of 14	NP_001490.1	B3KMG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLE1	ENST00000309971.9	TSL:1 MANE Select	c.727A>G	p.Ile243Val	missense	Exon 6 of 16	ENSP00000308622.5	Q53GS7-1
	GLE1	ENST00000372770.4	TSL:1	c.727A>G	p.Ile243Val	missense	Exon 6 of 14	ENSP00000361856.4	Q53GS7-2
	GLE1	ENST00000898507.1		c.727A>G	p.Ile243Val	missense	Exon 6 of 17	ENSP00000568566.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Lethal arthrogryposis-anterior horn cell disease syndrome (2)
-	-	2	Lethal congenital contracture syndrome 1 (2)
-	-	1	Lethal congenital contractural syndrome Finnish type (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00059	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.37	T
Polyphen		0.0	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;