3-81594018-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000158.4(GBE1):c.998A>G(p.Glu333Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E333V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.63

Publications

0 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: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000158.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-81594018-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

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.998A>G	p.Glu333Gly	missense	Exon 8 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.998A>G	p.Glu333Gly	missense	Exon 8 of 16	ENSP00000410833.2	Q04446
GBE1	ENST00000895874.1		c.998A>G	p.Glu333Gly	missense	Exon 8 of 16	ENSP00000565933.1
GBE1	ENST00000942742.1		c.992A>G	p.Glu331Gly	missense	Exon 8 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1264102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

632386

African (AFR)

AF:

0.00

AC:

AN:

29094

American (AMR)

AF:

0.00

AC:

AN:

36484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24318

East Asian (EAS)

AF:

0.00

AC:

AN:

36682

South Asian (SAS)

AF:

0.00

AC:

AN:

76092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

951896

Other (OTH)

AF:

0.00

AC:

AN:

53604

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Adult polyglucosan body disease (1)

Glycogen storage disease, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.2

PhyloP100

7.6

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.93

MutPred

0.69

Gain of MoRF binding (P = 0.0294)

MVP

0.96

MPC

0.22

ClinPred

1.0

GERP RS

5.7

Varity_R

0.89

gMVP

0.88

Mutation Taster

=5/95

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over