rs13320194

Positions:

• chr3-81670925-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000158.4(GBE1):​c.342C>T​(p.Tyr114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,565,734 control chromosomes in the GnomAD database, including 2,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1141 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1642 hom.)
• Consequence: GBE1 NM_000158.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.736

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-81670925-G-A is Benign according to our data. Variant chr3-81670925-G-A is described in ClinVar as [Benign]. Clinvar id is 255388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81670925-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.736 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.342C>T	p.Tyr114=	synonymous_variant	3/16	ENST00000429644.7
GBE1	XR_007095662.1	n.470C>T		non_coding_transcript_exon_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.342C>T	p.Tyr114=	synonymous_variant	3/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.219C>T	p.Tyr73=	synonymous_variant	3/16	2
GBE1	ENST00000477426.1	n.58C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12914 AN: 151998 Hom.: 1141 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0751

GnomAD3 exomes AF: 0.0397 AC: 7883 AN: 198448 Hom.: 371 AF XY: 0.0364 AC XY: 3918 AN XY: 107504

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0577

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.0562

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0314

GnomAD4 exome AF: 0.0322 AC: 45474 AN: 1413618 Hom.: 1642 Cov.: 28 AF XY: 0.0318 AC XY: 22305 AN XY: 700776

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0605

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.0867

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0422

GnomAD4 genome AF: 0.0850 AC: 12923 AN: 152116 Hom.: 1141 Cov.: 32 AF XY: 0.0831 AC XY: 6177 AN XY: 74358

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.0751

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.0739

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0753

Alfa AF: 0.0357 Hom.: 450

Bravo AF: 0.0960

Asia WGS AF: 0.0610 AC: 211 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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+	-	- -

Glycogen storage disease, type IV 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Adult polyglucosan body disease Benign:1

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. -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 23, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.3
DANN	Benign	0.47

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: rs13320194; hg19: chr3-81720076; COSMIC: COSV70097732;