rs17121403

chr1-99870421-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):c.686A>G(p.Gln229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,613,906 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (259 hom., cov: 32)
  • Exomes 𝑓: 0.022 (710 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.68

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018741786).
• BP6: Variant 1-99870421-A-G is Benign according to our data. Variant chr1-99870421-A-G is described in ClinVar as [Benign]. Clinvar id is 256749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.686A>G	p.Gln229Arg	missense_variant	6/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.686A>G	p.Gln229Arg	missense_variant	6/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6475 AN: 152160 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0953

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0599

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0338 AC: 8504 AN: 251232 Hom.: 333 AF XY: 0.0291 AC XY: 3951 AN XY: 135780

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.0269

Gnomad SAS exome AF: 0.0206

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0222 AC: 32486 AN: 1461628 Hom.: 710 Cov.: 32 AF XY: 0.0213 AC XY: 15520 AN XY: 727134

Gnomad4 AFR exome AF: 0.0968

Gnomad4 AMR exome AF: 0.0985

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0389

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.00646

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.0428 AC: 6513 AN: 152278 Hom.: 259 Cov.: 32 AF XY: 0.0430 AC XY: 3199 AN XY: 74462

Gnomad4 AFR AF: 0.0959

Gnomad4 AMR AF: 0.0601

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0234 Hom.: 176

Bravo AF: 0.0511

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.0188 AC: 162

ExAC AF: 0.0326 AC: 3953

Asia WGS AF: 0.0350 AC: 121 AN: 3476

EpiCase AF: 0.0168

EpiControl AF: 0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:5

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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.70
DEOGEN2	Benign	0.029	T;T;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.86	D;.;.;.;D
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N;N;N;N;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.40	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.86	T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.043
MPC		0.043
ClinPred		0.0016	T
GERP RS		4.2
Varity_R		0.039
gMVP		0.59

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: rs17121403; hg19: chr1-100335977;