rs62267114

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000158.4(GBE1):c.15G>A(p.Met5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,604,598 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3O:1

Conservation

PhyloP100: -0.644

Publications

3 publications found

Variant links:

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]

GBE1 Gene-Disease associations (from GenCC):

glycogen storage disease due to glycogen branching enzyme deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics, G2P, ClinGen
adult polyglucosan body disease
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

GBE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009051472).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1 link	n.143G>A		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7 link	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 16	1	NM_000158.4	ENSP00000410833.2

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000861

AC:

195

AN:

226356

AF XY:

0.000848

show subpopulations

Gnomad AFR exome

AF:

0.000397

Gnomad AMR exome

AF:

0.000768

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.000893

GnomAD4 exome

AF:

0.00154

AC:

2243

AN:

1452456

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1062

AN XY:

722230

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33288

American (AMR)

AF:

0.000692

AC:

AN:

43336

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39062

South Asian (SAS)

AF:

0.000128

AC:

AN:

85724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50872

Middle Eastern (MID)

AF:

0.000565

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00192

AC:

2126

AN:

1108984

Other (OTH)

AF:

0.00107

AC:

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152142

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000555

AC:

AN:

41442

American (AMR)

AF:

0.000785

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00203

AC:

138

AN:

68030

Other (OTH)

AF:

0.00239

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.000997

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00147

AC:

ExAC

AF:

0.000704

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 12, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a family with familial primary hyperparathyroidism in published literature (PMID: 27745835); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27745835) -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 02, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Glycogen storage disease, type IV

Uncertain:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Adult polyglucosan body disease

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Oct 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GBE1 c.15G>A (p.Met5Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 257704 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.15G>A in individuals affected with GBE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

GBE1-related disorder

Benign:1

Jan 31, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.0

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.080

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.31

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

-0.64

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.060

REVEL

Benign

0.024

Sift

Benign

0.55

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.12

MutPred

0.36

Gain of catalytic residue at M5 (P = 0.0053);

MVP

0.20

MPC

0.032

ClinPred

0.0026

GERP RS

1.4

PromoterAI

-0.24

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.48

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over