chr3-81594016-T-C

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.1000A>G(p.Ile334Val) variant causes a missense change. The variant allele was found at a frequency of 0.972 in 1,505,534 control chromosomes in the GnomAD database, including 711,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72929 hom., cov: 31)

Exomes 𝑓: 0.97 ( 638906 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.82

Publications

32 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 -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, 4 uncertain in NM_000158.4

BP4

Computational evidence support a benign effect (MetaRNN=7.2837616E-7).

BP6

Variant 3-81594016-T-C is Benign according to our data. Variant chr3-81594016-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.1000A>G	p.Ile334Val	missense_variant	Exon 8 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1 link	n.1128A>G		non_coding_transcript_exon_variant	Exon 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7 link	c.1000A>G	p.Ile334Val	missense_variant	Exon 8 of 16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1 link	c.877A>G	p.Ile293Val	missense_variant	Exon 8 of 16	2		ENSP00000419638.1

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148874

AN:

152116

Hom.:

72872

Cov.:

show subpopulations

Gnomad AFR

AF:

0.996

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.988

Gnomad ASJ

AF:

0.986

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.963

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.981

GnomAD2 exomes

AF:

0.976

AC:

178058

AN:

182518

AF XY:

0.974

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

0.990

Gnomad ASJ exome

AF:

0.988

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.959

Gnomad NFE exome

AF:

0.969

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.972

AC:

1314913

AN:

1353300

Hom.:

638906

Cov.:

AF XY:

0.971

AC XY:

653309

AN XY:

672632

show subpopulations

African (AFR)

AF:

0.997

AC:

30979

AN:

31084

American (AMR)

AF:

0.990

AC:

37095

AN:

37488

Ashkenazi Jewish (ASJ)

AF:

0.985

AC:

24510

AN:

24886

East Asian (EAS)

AF:

1.00

AC:

37371

AN:

37374

South Asian (SAS)

AF:

0.964

AC:

75296

AN:

78090

European-Finnish (FIN)

AF:

0.958

AC:

48660

AN:

50770

Middle Eastern (MID)

AF:

0.962

AC:

5405

AN:

5620

European-Non Finnish (NFE)

AF:

0.970

AC:

1000433

AN:

1031324

Other (OTH)

AF:

0.974

AC:

55164

AN:

56664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1590

3180

4771

6361

7951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19926

39852

59778

79704

99630

<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:

0.979

AC:

148990

AN:

152234

Hom.:

72929

Cov.:

AF XY:

0.978

AC XY:

72803

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.996

AC:

41370

AN:

41554

American (AMR)

AF:

0.988

AC:

15090

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.986

AC:

3423

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5169

AN:

5172

South Asian (SAS)

AF:

0.962

AC:

4648

AN:

4830

European-Finnish (FIN)

AF:

0.958

AC:

10157

AN:

10604

Middle Eastern (MID)

AF:

0.966

AC:

284

AN:

294

European-Non Finnish (NFE)

AF:

0.969

AC:

65867

AN:

68008

Other (OTH)

AF:

0.981

AC:

2074

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

159

318

477

636

795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.974

Hom.:

145098

Bravo

AF:

0.983

TwinsUK

AF:

0.972

AC:

3606

ALSPAC

AF:

0.972

AC:

3747

ESP6500AA

AF:

0.996

AC:

3602

ESP6500EA

AF:

0.972

AC:

7924

ExAC

AF:

0.969

AC:

112433

Asia WGS

AF:

0.984

AC:

3418

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glycogen storage disease, type IV

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adult polyglucosan body disease

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.051

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-3.1

N;.

PhyloP100

5.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.95

N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.062

MPC

0.028

ClinPred

0.012

GERP RS

5.7

Varity_R

0.033

gMVP

0.58

Mutation Taster

=98/2

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