chr9-128527566-G-A

Variant names:

• chr9-128527566-G-A
• rs41306469
• NM_001003722.2:c.1312+41G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001003722.2(GLE1):​c.1312+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,176,596 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 31)
  • Exomes 𝑓: 0.011 (89 hom.)
• Consequence: GLE1 NM_001003722.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.129
• Publications: 1 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 (BayesDel_noAF=-0.86).
• BP6: Variant 9-128527566-G-A is Benign according to our data. Variant chr9-128527566-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0159 (2417/152260) while in subpopulation AFR AF = 0.0259 (1075/41548). AF 95% confidence interval is 0.0246. There are 25 homozygotes in GnomAd4. There are 1135 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLE1	NM_001003722.2	c.1312+41G>A		intron_variant	Intron 9 of 15	ENST00000309971.9	NP_001003722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLE1	ENST00000309971.9	c.1312+41G>A		intron_variant	Intron 9 of 15	1	NM_001003722.2	ENSP00000308622.5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2418 AN: 152142 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0117 AC: 2928 AN: 249250 AF XY: 0.0114

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00908

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0111 AC: 11368 AN: 1024336 Hom.: 89 Cov.: 14 AF XY: 0.0109 AC XY: 5768 AN XY: 529070

African (AFR) AF: 0.0257 AC: 646 AN: 25118

American (AMR) AF: 0.0103 AC: 454 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 475 AN: 23392

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37698

South Asian (SAS) AF: 0.00690 AC: 533 AN: 77268

European-Finnish (FIN) AF: 0.00889 AC: 473 AN: 53230

Middle Eastern (MID) AF: 0.0373 AC: 183 AN: 4902

European-Non Finnish (NFE) AF: 0.0113 AC: 8059 AN: 712624

Other (OTH) AF: 0.0118 AC: 544 AN: 46048

GnomAD4 genome AF: 0.0159 AC: 2417 AN: 152260 Hom.: 25 Cov.: 31 AF XY: 0.0152 AC XY: 1135 AN XY: 74454

African (AFR) AF: 0.0259 AC: 1075 AN: 41548

American (AMR) AF: 0.0157 AC: 240 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4830

European-Finnish (FIN) AF: 0.00811 AC: 86 AN: 10602

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 68014

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0143 Hom.: 3

Bravo AF: 0.0173

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.9
DANN	Benign	0.47
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs41306469; hg19: chr9-131289845;