chr9-128522658-A-C

Variant names:

• chr9-128522658-A-C
• rs386833693
• NM_001003722.2:c.433-10A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001003722.2(GLE1):​c.433-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLE1 NM_001003722.2 intron
• Scores: Splicing: ADA: 0.0001725
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0570
• Publications: 5 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: 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 9-128522658-A-C is Benign according to our data. Variant chr9-128522658-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1561616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.433-10A>C		intron	N/A	NP_001003722.1	Q53GS7-1
	GLE1	NM_001411013.1		c.433-10A>C		intron	N/A	NP_001397942.1	A0A804HJ70
	GLE1	NM_001499.2		c.433-10A>C		intron	N/A	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.433-10A>C		intron	N/A	ENSP00000308622.5	Q53GS7-1
	GLE1	ENST00000372770.4	TSL:1	c.433-10A>C		intron	N/A	ENSP00000361856.4	Q53GS7-2
	GLE1	ENST00000898507.1		c.433-10A>C		intron	N/A	ENSP00000568566.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000216 AC: 3 AN: 1385912 Hom.: 0 Cov.: 38 AF XY: 0.00000290 AC XY: 2 AN XY: 689272

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30796

American (AMR) AF: 0.00 AC: 0 AN: 37456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24596

East Asian (EAS) AF: 0.00 AC: 0 AN: 37948

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80194

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065812

Other (OTH) AF: 0.0000175 AC: 1 AN: 57176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.9
DANN	Benign	0.65
PhyloP100		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.014
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: rs386833693; hg19: chr9-131284937;