chr9-128536414-G-T

Variant names:

• chr9-128536414-G-T
• rs121434407
• NM_001003722.2:c.1706G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001003722.2(GLE1):​c.1706G>T​(p.Arg569Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R569C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GLE1 NM_001003722.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.98
• Publications: 23 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

ENSG00000228395 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128536414-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.1706G>T	p.Arg569Leu	missense	Exon 12 of 16	NP_001003722.1	Q53GS7-1
	GLE1	NM_001411013.1		c.1733G>T	p.Arg578Leu	missense	Exon 13 of 17	NP_001397942.1	A0A804HJ70
	GLE1	NM_001499.2		c.1706G>T	p.Arg569Leu	missense	Exon 12 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.1706G>T	p.Arg569Leu	missense	Exon 12 of 16	ENSP00000308622.5	Q53GS7-1
	GLE1	ENST00000372770.4	TSL:1	c.1706G>T	p.Arg569Leu	missense	Exon 12 of 14	ENSP00000361856.4	Q53GS7-2
	GLE1	ENST00000898507.1		c.1763G>T	p.Arg588Leu	missense	Exon 13 of 17	ENSP00000568566.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Loss of MoRF binding (P = 0.0187)
MVP		0.98
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.96
Mutation Taster		=10/90	disease causing

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: rs121434407; hg19: chr9-131298693;