chr3-81499145-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000158.4(GBE1):c.2017G>A(p.Ala673Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,609,962 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 58 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.20

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044651926).

BP6

Variant 3-81499145-C-T is Benign according to our data. Variant chr3-81499145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81499145-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00514 (782/152188) while in subpopulation NFE AF = 0.00836 (568/67980). AF 95% confidence interval is 0.00779. There are 6 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.2017G>A	p.Ala673Thr	missense_variant	Exon 15 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7 link	c.2017G>A	p.Ala673Thr	missense_variant	Exon 15 of 16	1	NM_000158.4	ENSP00000410833.2		Q04446
GBE1	ENST00000489715.1 link	c.1894G>A	p.Ala632Thr	missense_variant	Exon 15 of 16	2		ENSP00000419638.1		E9PGM4

Frequencies

GnomAD3 genomes

AF:

0.00514

AC:

782

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00835

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00502

AC:

1235

AN:

246198

AF XY:

0.00521

show subpopulations

Gnomad AFR exome

AF:

0.00183

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00140

Gnomad EAS exome

AF:

0.0000563

Gnomad FIN exome

AF:

0.00285

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.00486

GnomAD4 exome

AF:

0.00809

AC:

11799

AN:

1457774

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

5790

AN XY:

725116

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

AC:

AN:

33402

Gnomad4 AMR exome

AF:

0.00272

AC:

121

AN:

44462

Gnomad4 ASJ exome

AF:

0.00138

AC:

AN:

26058

Gnomad4 EAS exome

AF:

0.0000253

AC:

AN:

39596

Gnomad4 SAS exome

AF:

0.00288

AC:

247

AN:

85696

Gnomad4 FIN exome

AF:

0.00328

AC:

175

AN:

53310

Gnomad4 NFE exome

AF:

0.00975

AC:

10813

AN:

1109236

Gnomad4 Remaining exome

AF:

0.00609

AC:

367

AN:

60250

Heterozygous variant carriers

499

998

1497

1996

2495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.00514

AC:

782

AN:

152188

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00130

AC:

0.00130001

AN:

0.00130001

Gnomad4 AMR

AF:

0.00655

AC:

0.00654536

AN:

0.00654536

Gnomad4 ASJ

AF:

0.00173

AC:

0.00172911

AN:

0.00172911

Gnomad4 EAS

AF:

0.000193

AC:

0.000192678

AN:

0.000192678

Gnomad4 SAS

AF:

0.00249

AC:

0.00249066

AN:

0.00249066

Gnomad4 FIN

AF:

0.00274

AC:

0.00273688

AN:

0.00273688

Gnomad4 NFE

AF:

0.00836

AC:

0.0083554

AN:

0.0083554

Gnomad4 OTH

AF:

0.00520

AC:

0.00520341

AN:

0.00520341

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00693

Hom.:

Bravo

AF:

0.00539

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00164

AC:

ESP6500EA

AF:

0.00660

AC:

ExAC

AF:

0.00496

AC:

599

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 10, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GBE1: BP4, BS2 -

May 20, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26670585, 31862442) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 17, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 08, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GBE1 c.2017G>A (p.Ala673Thr) results in a non-conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 277576 control chromosomes (gnomAD), predominantly at a frequency of 0.0083 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, and five as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

Benign:1

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease, type IV

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Adult polyglucosan body disease

Benign:1

Apr 27, 2017

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

0.073

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.72

N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.17

Sift

Benign

0.14

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.040

B;.

Vest4

0.13

MVP

0.58

MPC

0.030

ClinPred

0.015

GERP RS

-6.4

Varity_R

0.31

gMVP

0.26

Mutation Taster

=92/8

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over