rs17121466

Variant names:

• chr1-99875271-T-C
• rs17121466
• NM_000642.3:c.1185+15T>C

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.1185+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,612,916 control chromosomes in the GnomAD database, including 700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (52 hom., cov: 33)
  • Exomes 𝑓: 0.026 (648 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10
• Publications: 5 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=-0.83).
• BP6: Variant 1-99875271-T-C is Benign according to our data. Variant chr1-99875271-T-C is described in ClinVar as Benign. ClinVar VariationId is 256720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.1185+15T>C		intron_variant	Intron 9 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1185+15T>C		intron_variant	Intron 9 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3177 AN: 152216 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0308 AC: 7718 AN: 250610 AF XY: 0.0330

Gnomad AFR exome AF: 0.00495

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0366

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0260 AC: 38009 AN: 1460582 Hom.: 648 Cov.: 31 AF XY: 0.0276 AC XY: 20071 AN XY: 726666

African (AFR) AF: 0.00416 AC: 139 AN: 33446

American (AMR) AF: 0.0389 AC: 1740 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 608 AN: 26120

East Asian (EAS) AF: 0.0198 AC: 785 AN: 39668

South Asian (SAS) AF: 0.0719 AC: 6197 AN: 86232

European-Finnish (FIN) AF: 0.0115 AC: 615 AN: 53416

Middle Eastern (MID) AF: 0.0269 AC: 155 AN: 5768

European-Non Finnish (NFE) AF: 0.0236 AC: 26236 AN: 1110906

Other (OTH) AF: 0.0254 AC: 1534 AN: 60330

GnomAD4 genome AF: 0.0209 AC: 3184 AN: 152334 Hom.: 52 Cov.: 33 AF XY: 0.0224 AC XY: 1667 AN XY: 74496

African (AFR) AF: 0.00455 AC: 189 AN: 41576

American (AMR) AF: 0.0419 AC: 641 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3466

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5188

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4828

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1583 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0232 Hom.: 25

Bravo AF: 0.0210

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:3

Jan 13, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 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

- -

Jan 23, 2016

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

- -

Dec 16, 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	-0.83
CADD	Benign	13
DANN	Benign	0.60
PhyloP100		3.1
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: rs17121466; hg19: chr1-100340827;