rs758562610

Variant names:

• chr1-99900819-G-A
• rs758562610
• NM_000642.3:c.3546G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-99900819-G-A
• chr1-99900819-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000642.3(AGL):​c.3546G>A​(p.Met1182Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

AGL Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3266919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.3546G>A	p.Met1182Ile	missense_variant	Exon 26 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3546G>A	p.Met1182Ile	missense_variant	Exon 26 of 34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with isoleucine at codon 1182 of the AGL protein (p.Met1182Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with AGL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3546G>A (p.M1182I) alteration is located in exon 26 (coding exon 25) of the AGL gene. This alteration results from a G to A substitution at nucleotide position 3546, causing the methionine (M) at amino acid position 1182 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Benign	0.054	T;T;T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;.;.;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N;N;N;N;.
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.060	N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.98	T;T;T;T;T
Polyphen		0.0030	B;B;B;B;B
Vest4		0.59
MutPred		0.50		Gain of catalytic residue at P1184 (P = 0.03);Gain of catalytic residue at P1184 (P = 0.03);Gain of catalytic residue at P1184 (P = 0.03);Gain of catalytic residue at P1184 (P = 0.03);.;
MVP		0.69
MPC		0.046
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.57
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758562610; hg19: chr1-100366375;