rs555929

Variant names:

• chr1-99888119-G-A
• rs555929
• NM_000642.3:c.2812+11G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.2812+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,611,480 control chromosomes in the GnomAD database, including 385,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33533 hom., cov: 30)
  • Exomes 𝑓: 0.69 (352337 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.237
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-99888119-G-A is Benign according to our data. Variant chr1-99888119-G-A is described in ClinVar as Benign. ClinVar VariationId is 256730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.2812+11G>A		intron_variant	Intron 21 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.2812+11G>A		intron_variant	Intron 21 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100513 AN: 151778 Hom.: 33501 Cov.: 30

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.670

GnomAD2 exomes AF: 0.690 AC: 173003 AN: 250574 AF XY: 0.693

Gnomad AFR exome AF: 0.585

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.689

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.694 AC: 1012703 AN: 1459582 Hom.: 352337 Cov.: 51 AF XY: 0.694 AC XY: 504198 AN XY: 726160

African (AFR) AF: 0.582 AC: 19432 AN: 33412

American (AMR) AF: 0.719 AC: 32074 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 16110 AN: 26076

East Asian (EAS) AF: 0.706 AC: 27960 AN: 39604

South Asian (SAS) AF: 0.730 AC: 62909 AN: 86202

European-Finnish (FIN) AF: 0.692 AC: 36545 AN: 52784

Middle Eastern (MID) AF: 0.660 AC: 3798 AN: 5754

European-Non Finnish (NFE) AF: 0.696 AC: 773055 AN: 1110812

Other (OTH) AF: 0.677 AC: 40820 AN: 60298

GnomAD4 genome AF: 0.662 AC: 100588 AN: 151898 Hom.: 33533 Cov.: 30 AF XY: 0.665 AC XY: 49355 AN XY: 74264

African (AFR) AF: 0.582 AC: 24074 AN: 41396

American (AMR) AF: 0.695 AC: 10607 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2081 AN: 3462

East Asian (EAS) AF: 0.700 AC: 3614 AN: 5166

South Asian (SAS) AF: 0.746 AC: 3580 AN: 4802

European-Finnish (FIN) AF: 0.691 AC: 7295 AN: 10560

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.693 AC: 47108 AN: 67936

Other (OTH) AF: 0.675 AC: 1425 AN: 2112

Alfa AF: 0.673 Hom.: 22183

Bravo AF: 0.655

Asia WGS AF: 0.730 AC: 2540 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.032
DANN	Benign	0.32
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs555929; hg19: chr1-100353675; COSMIC: COSV54049809;