rs17019144

Positions:

• chr3-81648968-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000429644.7(GBE1):​c.579G>A​(p.Lys193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,584,236 control chromosomes in the GnomAD database, including 3,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1200 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1945 hom.)
• Consequence: GBE1 ENST00000429644.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-81648968-C-T is Benign according to our data. Variant chr3-81648968-C-T is described in ClinVar as [Benign]. Clinvar id is 255390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81648968-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.579G>A	p.Lys193=	synonymous_variant	5/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.707G>A		non_coding_transcript_exon_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.579G>A	p.Lys193=	synonymous_variant	5/16	1	NM_000158.4	ENSP00000410833	P1
GBE1	ENST00000489715.1	c.456G>A	p.Lys152=	synonymous_variant	5/16	2		ENSP00000419638
GBE1	ENST00000486920.1	n.575G>A		non_coding_transcript_exon_variant	2/2	3
GBE1	ENST00000498468.1	n.107G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13571 AN: 151992 Hom.: 1199 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0736

Gnomad SAS AF: 0.0527

Gnomad FIN AF: 0.00811

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0774

GnomAD3 exomes AF: 0.0467 AC: 10447 AN: 223806 Hom.: 506 AF XY: 0.0434 AC XY: 5262 AN XY: 121336

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.0595

Gnomad SAS exome AF: 0.0551

Gnomad FIN exome AF: 0.00570

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0368 AC: 52651 AN: 1432126 Hom.: 1945 Cov.: 26 AF XY: 0.0367 AC XY: 26118 AN XY: 711414

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0641

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.0865

Gnomad4 SAS exome AF: 0.0550

Gnomad4 FIN exome AF: 0.00797

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0470

GnomAD4 genome AF: 0.0893 AC: 13584 AN: 152110 Hom.: 1200 Cov.: 32 AF XY: 0.0875 AC XY: 6509 AN XY: 74354

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.0820

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.0734

Gnomad4 SAS AF: 0.0525

Gnomad4 FIN AF: 0.00811

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0776

Alfa AF: 0.0459 Hom.: 171

Bravo AF: 0.0997

Asia WGS AF: 0.0680 AC: 236 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
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 13, 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
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.1
DANN	Benign	0.65

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

Other links and lift over

dbSNP: rs17019144; hg19: chr3-81698119;