rs594249

Variant names:

• chr1-99892644-G-A
• rs594249
• NM_000642.3:c.3259+37G>A

Variant summary

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

The ENST00000361915.8(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 ENST00000361915.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.87
• Publications: 10 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=-0.96).
• BP6: Variant 1-99892644-G-A is Benign according to our data. Variant chr1-99892644-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361915.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.3259+37G>A		intron	N/A	NP_000633.2
	AGL	NM_000028.3		c.3259+37G>A		intron	N/A	NP_000019.2
	AGL	NM_000643.3		c.3259+37G>A		intron	N/A	NP_000634.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.3259+37G>A		intron	N/A	ENSP00000355106.3
	AGL	ENST00000294724.8	TSL:1	c.3259+37G>A		intron	N/A	ENSP00000294724.4
	AGL	ENST00000370163.7	TSL:1	c.3259+37G>A		intron	N/A	ENSP00000359182.3

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

GnomAD2 exomes AF: 0.691 AC: 171182 AN: 247704 AF XY: 0.693

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 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

African (AFR) AF: 0.582 AC: 19095 AN: 32832

American (AMR) AF: 0.719 AC: 31958 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 16017 AN: 25930

East Asian (EAS) AF: 0.706 AC: 27865 AN: 39456

South Asian (SAS) AF: 0.734 AC: 62858 AN: 85622

European-Finnish (FIN) AF: 0.692 AC: 36450 AN: 52688

Middle Eastern (MID) AF: 0.669 AC: 3823 AN: 5714

European-Non Finnish (NFE) AF: 0.696 AC: 759841 AN: 1091148

Other (OTH) AF: 0.677 AC: 40269 AN: 59466

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

African (AFR) AF: 0.582 AC: 24118 AN: 41446

American (AMR) AF: 0.695 AC: 10634 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2081 AN: 3464

East Asian (EAS) AF: 0.701 AC: 3627 AN: 5176

South Asian (SAS) AF: 0.749 AC: 3618 AN: 4828

European-Finnish (FIN) AF: 0.692 AC: 7312 AN: 10568

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

European-Non Finnish (NFE) AF: 0.694 AC: 47130 AN: 67952

Other (OTH) AF: 0.676 AC: 1425 AN: 2108

Alfa AF: 0.681 Hom.: 20187

Bravo AF: 0.656

Asia WGS AF: 0.731 AC: 2540 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease type III (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.025
DANN	Benign	0.45
PhyloP100		-1.9
Mutation Taster		=14/86	disease causing

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