rs594249

chr1-99892644-G-A

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.3259+37G>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 1,589,346 control chromosomes in the GnomAD database, including 381,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33611 hom., cov: 33)
  • Exomes 𝑓: 0.69 (347684 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.87

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=-0.96).
• BP6: Variant 1-99892644-G-A is Benign according to our data. Variant chr1-99892644-G-A is described in ClinVar as [Benign]. Clinvar id is 256735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.3259+37G>A		intron_variant		ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.3259+37G>A		intron_variant		1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100673 AN: 151924 Hom.: 33579 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.672

GnomAD3 exomes AF: 0.691 AC: 171182 AN: 247704 Hom.: 59376 AF XY: 0.693 AC XY: 93065 AN XY: 134212

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.735

Gnomad FIN exome AF: 0.681

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.692

GnomAD4 exome AF: 0.694 AC: 998176 AN: 1437304 Hom.: 347684 Cov.: 26 AF XY: 0.695 AC XY: 498117 AN XY: 716568

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.719

Gnomad4 ASJ exome AF: 0.618

Gnomad4 EAS exome AF: 0.706

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.696

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.663 AC: 100749 AN: 152042 Hom.: 33611 Cov.: 33 AF XY: 0.665 AC XY: 49439 AN XY: 74312

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.695

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.701

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.676

Alfa AF: 0.682 Hom.: 18249

Bravo AF: 0.656

Asia WGS AF: 0.731 AC: 2540 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

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. -

Glycogen storage disease type III Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.025
Dann	Benign	0.45

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: rs594249; hg19: chr1-100358200; COSMIC: COSV54049828;