3-81648979-T-C

Position:

chr3-81648979-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.568A>G(p.Arg190Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,571,242 control chromosomes in the GnomAD database, including 75,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6997 hom., cov: 32)

Exomes 𝑓: 0.31 ( 68475 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 3.51

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:

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=0.002937764).

BP6

Variant 3-81648979-T-C is Benign according to our data. Variant chr3-81648979-T-C is described in ClinVar as [Benign]. Clinvar id is 197636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81648979-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 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.568A>G	p.Arg190Gly	missense_variant	5/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1 linkuse as main transcript	n.696A>G		non_coding_transcript_exon_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GBE1	ENST00000429644.7 linkuse as main transcript	c.568A>G	p.Arg190Gly	missense_variant	5/16	1	NM_000158.4	ENSP00000410833	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.445A>G	p.Arg149Gly	missense_variant	5/16	2		ENSP00000419638
GBE1	ENST00000486920.1 linkuse as main transcript	n.564A>G		non_coding_transcript_exon_variant	2/2	3
GBE1	ENST00000498468.1 linkuse as main transcript	n.96A>G		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45374

AN:

151906

Hom.:

6994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.270

GnomAD3 exomes

AF:

0.317

AC:

70584

AN:

222350

Hom.:

11554

AF XY:

0.316

AC XY:

38030

AN XY:

120320

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.452

Gnomad SAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.305

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.306

AC:

434420

AN:

1419218

Hom.:

68475

Cov.:

AF XY:

0.305

AC XY:

215363

AN XY:

705024

show subpopulations

Gnomad4 AFR exome

AF:

0.275

Gnomad4 AMR exome

AF:

0.292

Gnomad4 ASJ exome

AF:

0.206

Gnomad4 EAS exome

AF:

0.432

Gnomad4 SAS exome

AF:

0.296

Gnomad4 FIN exome

AF:

0.414

Gnomad4 NFE exome

AF:

0.302

Gnomad4 OTH exome

AF:

0.301

GnomAD4 genome

AF:

0.299

AC:

45395

AN:

152024

Hom.:

6997

Cov.:

AF XY:

0.303

AC XY:

22480

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.259

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.444

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.402

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.271

Alfa

AF:

0.295

Hom.:

14831

Bravo

AF:

0.290

TwinsUK

AF:

0.309

AC:

1144

ALSPAC

AF:

0.304

AC:

1170

ESP6500AA

AF:

0.277

AC:

992

ESP6500EA

AF:

0.301

AC:

2441

ExAC

AF:

0.306

AC:

36856

Asia WGS

AF:

0.391

AC:

1360

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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. -

Glycogen storage disease, type IV

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Adult polyglucosan body disease

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
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	Oct 20, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.42

P;P

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.066

T;T

Polyphen

0.013

B;B

Vest4

0.089

MPC

0.041

ClinPred

0.056

GERP RS

4.8

Varity_R

0.37

gMVP

0.68

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