rs9820490

Positions:

• chr3-81761365-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000158.4(GBE1):​c.143+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,601,546 control chromosomes in the GnomAD database, including 19,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1324 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18594 hom.)
• Consequence: GBE1 NM_000158.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.83

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-81761365-C-A is Benign according to our data. Variant chr3-81761365-C-A is described in ClinVar as [Benign]. Clinvar id is 255382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81761365-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.143+10G>T		intron_variant		ENST00000429644.7
GBE1	XR_007095662.1	n.271+10G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.143+10G>T		intron_variant		1	NM_000158.4	P1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18760 AN: 152150 Hom.: 1325 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.122 AC: 29371 AN: 241116 Hom.: 2079 AF XY: 0.122 AC XY: 16093 AN XY: 131396

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.0721

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.0722

Gnomad SAS exome AF: 0.0666

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.155 AC: 224887 AN: 1449278 Hom.: 18594 Cov.: 33 AF XY: 0.153 AC XY: 109970 AN XY: 719284

Gnomad4 AFR exome AF: 0.0596

Gnomad4 AMR exome AF: 0.0774

Gnomad4 ASJ exome AF: 0.0828

Gnomad4 EAS exome AF: 0.0703

Gnomad4 SAS exome AF: 0.0668

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.123 AC: 18762 AN: 152268 Hom.: 1324 Cov.: 33 AF XY: 0.119 AC XY: 8873 AN XY: 74454

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0832

Gnomad4 EAS AF: 0.0764

Gnomad4 SAS AF: 0.0656

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.135

Alfa AF: 0.133 Hom.: 647

Bravo AF: 0.120

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glycogen storage disease, type IV Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Adult polyglucosan body disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.13
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs9820490; hg19: chr3-81810516; COSMIC: COSV70101000; COSMIC: COSV70101000;