NM_000158.4:c.1519A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000158.4(GBE1):c.1519A>G(p.Thr507Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,609,436 control chromosomes in the GnomAD database, including 1,845 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T507T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 541 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1304 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0520

Publications

16 publications found

Variant links:

COSMIC-nc: COSV107525203

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 -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000158.4

BP4

Computational evidence support a benign effect (MetaRNN=0.001793772).

BP6

Variant 3-81578024-T-C is Benign according to our data. Variant chr3-81578024-T-C is described in ClinVar as Benign. ClinVar VariationId is 255383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.1519A>G	p.Thr507Ala	missense_variant	Exon 12 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.1647A>G		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GBE1	ENST00000429644.7 link	c.1519A>G	p.Thr507Ala	missense_variant	Exon 12 of 16	1	NM_000158.4	ENSP00000410833.2	Q04446
GBE1	ENST00000489715.1 link	c.1396A>G	p.Thr466Ala	missense_variant	Exon 12 of 16	2		ENSP00000419638.1	E9PGM4
GBE1	ENST00000484687.1 link	n.-81A>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9872

AN:

151738

Hom.:

539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0704

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0618

GnomAD2 exomes

AF:

0.0420

AC:

10239

AN:

243764

AF XY:

0.0400

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0607

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0502

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0367

GnomAD4 exome

AF:

0.0334

AC:

48730

AN:

1457580

Hom.:

1304

Cov.:

AF XY:

0.0335

AC XY:

24277

AN XY:

724906

show subpopulations

African (AFR)

AF:

0.144

AC:

4772

AN:

33206

American (AMR)

AF:

0.0615

AC:

2706

AN:

44006

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

455

AN:

26072

East Asian (EAS)

AF:

0.0815

AC:

3216

AN:

39476

South Asian (SAS)

AF:

0.0486

AC:

4149

AN:

85340

European-Finnish (FIN)

AF:

0.0319

AC:

1703

AN:

53336

Middle Eastern (MID)

AF:

0.0686

AC:

395

AN:

5762

European-Non Finnish (NFE)

AF:

0.0262

AC:

29045

AN:

1110134

Other (OTH)

AF:

0.0380

AC:

2289

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2232

4464

6697

8929

11161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1248

2496

3744

4992

6240

<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:

0.0650

AC:

9877

AN:

151856

Hom.:

541

Cov.:

AF XY:

0.0653

AC XY:

4846

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.142

AC:

5873

AN:

41380

American (AMR)

AF:

0.0702

AC:

1068

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

AN:

3472

East Asian (EAS)

AF:

0.0628

AC:

324

AN:

5160

South Asian (SAS)

AF:

0.0423

AC:

203

AN:

4804

European-Finnish (FIN)

AF:

0.0313

AC:

329

AN:

10524

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0270

AC:

1836

AN:

67984

Other (OTH)

AF:

0.0621

AC:

131

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

440

881

1321

1762

2202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0394

Hom.:

758

Bravo

AF:

0.0700

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0285

AC:

110

ESP6500AA

AF:

0.120

AC:

467

ESP6500EA

AF:

0.0229

AC:

190

ExAC

AF:

0.0431

AC:

5210

Asia WGS

AF:

0.0600

AC:

211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glycogen storage disease, type IV

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:2

Mar 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Adult polyglucosan body disease

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

0.052

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.26

Sift

Benign

0.30

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.0080

MPC

0.030

ClinPred

0.017

GERP RS

-5.5

Varity_R

0.13

gMVP

0.45

Mutation Taster

=100/0

polymorphism (auto)

(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