rs17121466

Positions:

• chr1-99875271-T-C

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.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:6
• Conservation: PhyloP100: 3.10

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 (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 id is 256720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99875271-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
AGL	NM_000642.3	c.1185+15T>C		intron_variant		ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.1185+15T>C		intron_variant		1	NM_000642.3	P1

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

GnomAD3 exomes AF: 0.0308 AC: 7718 AN: 250610 Hom.: 175 AF XY: 0.0330 AC XY: 4474 AN XY: 135654

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 SAS exome AF: 0.0723

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

Gnomad4 AFR exome AF: 0.00416

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.0198

Gnomad4 SAS exome AF: 0.0719

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0236

Gnomad4 OTH exome AF: 0.0254

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

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.0326

Gnomad4 SAS AF: 0.0694

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0224 Hom.: 17

Bravo AF: 0.0210

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2016	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 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.60

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: rs17121466; hg19: chr1-100340827;