rs2228389

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000158.4(GBE1):c.1519A>T(p.Thr507Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,457,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T507A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0520

Publications

16 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: Uncertain_significance. The variant received 5 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, 8 uncertain in NM_000158.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1519A>T	p.Thr507Ser	missense	Exon 12 of 16	NP_000149.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1519A>T	p.Thr507Ser	missense	Exon 12 of 16	ENSP00000410833.2
GBE1	ENST00000895874.1		c.1513A>T	p.Thr505Ser	missense	Exon 12 of 16	ENSP00000565933.1
GBE1	ENST00000942742.1		c.1513A>T	p.Thr505Ser	missense	Exon 12 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1457750

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33230

American (AMR)

AF:

0.00

AC:

AN:

44038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1110206

Other (OTH)

AF:

0.00

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.71

M_CAP

Benign

0.025

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.28

PhyloP100

0.052

PrimateAI

Benign

0.27

PROVEAN

Benign

0.020

REVEL

Benign

0.14

Sift

Benign

0.92

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.051

MutPred

0.24

Gain of helix (P = 0.132)

MVP

0.56

MPC

0.029

ClinPred

0.025

GERP RS

-5.5

Varity_R

0.11

gMVP

0.40

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.67

Position offset: -16

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over