rs62267114

Variant names:

• chr3-81761503-C-T
• rs62267114
• NM_000158.4:c.15G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000158.4(GBE1):​c.15G>A​(p.Met5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,604,598 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3 O:1
• Conservation: PhyloP100: -0.644

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009051472).
• BP6: Variant 3-81761503-C-T is Benign according to our data. Variant chr3-81761503-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 441107.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, not_provided=1, Likely_benign=2}. Variant chr3-81761503-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.143G>A		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 16	1	NM_000158.4	ENSP00000410833.2

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152142 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000861 AC: 195 AN: 226356 AF XY: 0.000848

Gnomad AFR exome AF: 0.000397

Gnomad AMR exome AF: 0.000768

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000893

GnomAD4 exome AF: 0.00154 AC: 2243 AN: 1452456 Hom.: 2 Cov.: 33 AF XY: 0.00147 AC XY: 1062 AN XY: 722230

Gnomad4 AFR exome AF: 0.000240 AC: 8 AN: 33288

Gnomad4 AMR exome AF: 0.000692 AC: 30 AN: 43336

Gnomad4 ASJ exome AF: 0.0000385 AC: 1 AN: 25980

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39062

Gnomad4 SAS exome AF: 0.000128 AC: 11 AN: 85724

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50872

Gnomad4 NFE exome AF: 0.00192 AC: 2126 AN: 1108984

Gnomad4 Remaining exome AF: 0.00107 AC: 64 AN: 59898

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152142 Hom.: 1 Cov.: 34 AF XY: 0.00112 AC XY: 83 AN XY: 74320

Gnomad4 AFR AF: 0.000555 AC: 0.000554993 AN: 0.000554993

Gnomad4 AMR AF: 0.000785 AC: 0.000785032 AN: 0.000785032

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00203 AC: 0.00202852 AN: 0.00202852

Gnomad4 OTH AF: 0.00239 AC: 0.00238777 AN: 0.00238777

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000997

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00147 AC: 12

ExAC AF: 0.000704 AC: 83

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Aug 02, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a family with familial primary hyperparathyroidism in published literature (PMID: 27745835); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27745835) -

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease Uncertain:2

Oct 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type IV Uncertain:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Adult polyglucosan body disease Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Oct 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBE1 c.15G>A (p.Met5Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 257704 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.15G>A in individuals affected with GBE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

GBE1-related disorder Benign:1

Jan 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.0
DANN	Benign	0.93
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.024
Sift	Benign	0.55	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.36		Gain of catalytic residue at M5 (P = 0.0053);
MVP		0.20
MPC		0.032
ClinPred		0.0026	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.48
Mutation Taster		=98/2	polymorphism

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: rs62267114; hg19: chr3-81810654;