rs193074572

chr3-81499145-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000158.4(GBE1):c.2017G>A(p.Ala673Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,609,962 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (58 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.20

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044651926).
• BP6: Variant 3-81499145-C-T is Benign according to our data. Variant chr3-81499145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81499145-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.2017G>A	p.Ala673Thr	missense_variant	15/16	ENST00000429644.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.2017G>A	p.Ala673Thr	missense_variant	15/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.1894G>A	p.Ala632Thr	missense_variant	15/16	2

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152070 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00835

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00502 AC: 1235 AN: 246198 Hom.: 5 AF XY: 0.00521 AC XY: 695 AN XY: 133462

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.00250

Gnomad FIN exome AF: 0.00285

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00809 AC: 11799 AN: 1457774 Hom.: 58 Cov.: 29 AF XY: 0.00798 AC XY: 5790 AN XY: 725116

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00272

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00975

Gnomad4 OTH exome AF: 0.00609

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152188 Hom.: 6 Cov.: 32 AF XY: 0.00482 AC XY: 359 AN XY: 74412

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00655

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.00836

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00716 Hom.: 4

Bravo AF: 0.00539

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00164 AC: 6

ESP6500EA AF: 0.00660 AC: 54

ExAC AF: 0.00496 AC: 599

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	This variant is associated with the following publications: (PMID: 26670585, 31862442) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GBE1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2022	Variant summary: GBE1 c.2017G>A (p.Ala673Thr) results in a non-conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 277576 control chromosomes (gnomAD), predominantly at a frequency of 0.0083 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, and five as benign. Based on the evidence outlined above, the variant was classified as benign. -

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Glycogen storage disease, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Adult polyglucosan body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.72	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.040	B;.
Vest4		0.13
MVP		0.58
MPC		0.030
ClinPred		0.015	T
GERP RS		-6.4
Varity_R		0.31
gMVP		0.26

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: rs193074572; hg19: chr3-81548296;