rs2307129

chr1-99861470-C-T

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.83-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,611,300 control chromosomes in the GnomAD database, including 28,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5046 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23743 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.01

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=-0.87).
• BP6: Variant 1-99861470-C-T is Benign according to our data. Variant chr1-99861470-C-T is described in ClinVar as [Benign]. Clinvar id is 256750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99861470-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.83-33C>T		intron_variant		ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.83-33C>T		intron_variant		1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35761 AN: 151892 Hom.: 5048 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.184 AC: 45917 AN: 249460 Hom.: 4712 AF XY: 0.183 AC XY: 24724 AN XY: 134856

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.175 AC: 254822 AN: 1459290 Hom.: 23743 Cov.: 33 AF XY: 0.175 AC XY: 127188 AN XY: 725964

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.193

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.235 AC: 35761 AN: 152010 Hom.: 5046 Cov.: 32 AF XY: 0.234 AC XY: 17424 AN XY: 74310

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.225

Alfa AF: 0.188 Hom.: 6117

Bravo AF: 0.238

Asia WGS AF: 0.165 AC: 573 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	-	- -

Glycogen storage disease type III Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.1
Dann	Benign	0.62

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: rs2307129; hg19: chr1-100327026; COSMIC: COSV54053030;