3-81578024-T-C

Position:

chr3-81578024-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000158.4(GBE1):c.1519A>G(p.Thr507Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,609,436 control chromosomes in the GnomAD database, including 1,845 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T507T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 541 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1304 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0520

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:

GBE1 (HGNC:):

GBE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001793772).

BP6

Variant 3-81578024-T-C is Benign according to our data. Variant chr3-81578024-T-C is described in ClinVar as [Benign]. Clinvar id is 255383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81578024-T-C is described in Lovd as [Benign]. Variant chr3-81578024-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.1519A>G	p.Thr507Ala	missense_variant	12/16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 linkuse as main transcript	n.1647A>G		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7 linkuse as main transcript	c.1519A>G	p.Thr507Ala	missense_variant	12/16	1	NM_000158.4	ENSP00000410833.2		Q04446
GBE1	ENST00000489715.1 linkuse as main transcript	c.1396A>G	p.Thr466Ala	missense_variant	12/16	2		ENSP00000419638.1		E9PGM4

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9872

AN:

151738

Hom.:

539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0704

Gnomad ASJ

AF:

0.0158

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0618

GnomAD3 exomes

AF:

0.0420

AC:

10239

AN:

243764

Hom.:

339

AF XY:

0.0400

AC XY:

5289

AN XY:

132276

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0607

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0502

Gnomad SAS exome

AF:

0.0483

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0367

GnomAD4 exome

AF:

0.0334

AC:

48730

AN:

1457580

Hom.:

1304

Cov.:

AF XY:

0.0335

AC XY:

24277

AN XY:

724906

show subpopulations

Gnomad4 AFR exome

AF:

0.144

Gnomad4 AMR exome

AF:

0.0615

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.0815

Gnomad4 SAS exome

AF:

0.0486

Gnomad4 FIN exome

AF:

0.0319

Gnomad4 NFE exome

AF:

0.0262

Gnomad4 OTH exome

AF:

0.0380

GnomAD4 genome

AF:

0.0650

AC:

9877

AN:

151856

Hom.:

541

Cov.:

AF XY:

0.0653

AC XY:

4846

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.142

Gnomad4 AMR

AF:

0.0702

Gnomad4 ASJ

AF:

0.0158

Gnomad4 EAS

AF:

0.0628

Gnomad4 SAS

AF:

0.0423

Gnomad4 FIN

AF:

0.0313

Gnomad4 NFE

AF:

0.0270

Gnomad4 OTH

AF:

0.0621

Alfa

AF:

0.0337

Hom.:

251

Bravo

AF:

0.0700

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0285

AC:

110

ESP6500AA

AF:

0.120

AC:

467

ESP6500EA

AF:

0.0229

AC:

190

ExAC

AF:

0.0431

AC:

5210

Asia WGS

AF:

0.0600

AC:

211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Glycogen storage disease, type IV

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adult polyglucosan body disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.26

Sift

Benign

0.30

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;B

Vest4

0.0080

MPC

0.030

ClinPred

0.017

GERP RS

-5.5

Varity_R

0.13

gMVP

0.45

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