rs35196441

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.118C>A(p.Pro40Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,612,950 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 19 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.94

Publications

8 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: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
adult polyglucosan body disease
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

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=0.008630902).

BP6

Variant 3-81761400-G-T is Benign according to our data. Variant chr3-81761400-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (827/152372) while in subpopulation AFR AF = 0.0148 (617/41600). AF 95% confidence interval is 0.0139. There are 7 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.118C>A	p.Pro40Thr	missense	Exon 1 of 16	NP_000149.4	Q04446

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBE1	ENST00000429644.7	TSL:1 MANE Select	c.118C>A	p.Pro40Thr	missense	Exon 1 of 16	ENSP00000410833.2	Q04446
GBE1	ENST00000895874.1		c.118C>A	p.Pro40Thr	missense	Exon 1 of 16	ENSP00000565933.1
GBE1	ENST00000942742.1		c.118C>A	p.Pro40Thr	missense	Exon 1 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

817

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00253

AC:

625

AN:

247310

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000690

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00137

AC:

1997

AN:

1460578

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1008

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.0152

AC:

505

AN:

33280

American (AMR)

AF:

0.00201

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

637

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000477

AC:

530

AN:

1111236

Other (OTH)

AF:

0.00360

AC:

217

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00543

AC:

827

AN:

152372

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

388

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0148

AC:

617

AN:

41600

American (AMR)

AF:

0.00477

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68036

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

124

165

206

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:

0.00330

Hom.:

Bravo

AF:

0.00637

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.00168

AC:

ExAC

AF:

0.00233

AC:

282

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Glycogen storage disease, type IV (4)

not specified (3)

Adult polyglucosan body disease (1)

GBE1-related disorder (1)

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Benign

0.015

Eigen_PC

Benign

0.097

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

PhyloP100

3.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.092

Sift

Uncertain

0.018

Sift4G

Uncertain

0.032

Polyphen

0.047

Vest4

0.46

MVP

0.47

MPC

0.034

ClinPred

0.059

GERP RS

3.9

PromoterAI

0.052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.65

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over