Genetic Variant GLE1:p.Gly666Ala (chr9-128540307-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001003722.2(GLE1):c.1997G>C(p.Gly666Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. G666V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GLE1
NM_001003722.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.14

Publications

0 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:

ENSG00000228395 (HGNC:):

ENSG00000228395 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3997454).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
GLE1	NM_001003722.2	MANE Select	c.1997G>C	p.Gly666Ala	missense	Exon 15 of 16	NP_001003722.1	Q53GS7-1
GLE1	NM_001411013.1		c.2024G>C	p.Gly675Ala	missense	Exon 16 of 17	NP_001397942.1	A0A804HJ70
LOC101929270	NR_188457.1		n.352+3072C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLE1	ENST00000309971.9	TSL:1 MANE Select	c.1997G>C	p.Gly666Ala	missense	Exon 15 of 16	ENSP00000308622.5	Q53GS7-1
GLE1	ENST00000898507.1		c.2054G>C	p.Gly685Ala	missense	Exon 16 of 17	ENSP00000568566.1
GLE1	ENST00000898511.1		c.2027G>C	p.Gly676Ala	missense	Exon 15 of 16	ENSP00000568570.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108714

Other (OTH)

AF:

0.00

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.021

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.9

PhyloP100

7.1

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.32

Sift

Benign

0.063

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.49

MutPred

0.39

Gain of catalytic residue at Q664 (P = 0.1138)

MVP

0.81

MPC

0.69

ClinPred

0.98

GERP RS

5.7

Varity_R

0.39

gMVP

0.68

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over