rs2307130

chr1-99851033-A-Gchr1-99851033-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The ENST00000370165.7(AGL):c.-8-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,610,628 control chromosomes in the GnomAD database, including 191,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14097 hom., cov: 33)
  • Exomes 𝑓: 0.49 (177867 hom.)
• Consequence: AGL ENST00000370165.7 splice_acceptor
• Scores: Splicing: ADA: 0.0001780
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.357

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 -14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.019352034 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of -16, new splice context is: tcttttaattcttatgaaAGatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 1-99851033-A-G is Benign according to our data. Variant chr1-99851033-A-G is described in ClinVar as [Benign]. Clinvar id is 195096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99851033-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.-10A>G		5_prime_UTR_variant	2/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.-10A>G		5_prime_UTR_variant	2/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63647 AN: 151976 Hom.: 14073 Cov.: 33

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.422

GnomAD3 exomes AF: 0.469 AC: 117972 AN: 251340 Hom.: 28421 AF XY: 0.479 AC XY: 65025 AN XY: 135874

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.534

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.491 AC: 715475 AN: 1458534 Hom.: 177867 Cov.: 31 AF XY: 0.493 AC XY: 357476 AN XY: 725786

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.545

Gnomad4 SAS exome AF: 0.538

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.419 AC: 63701 AN: 152094 Hom.: 14097 Cov.: 33 AF XY: 0.420 AC XY: 31205 AN XY: 74338

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.545

Gnomad4 SAS AF: 0.545

Gnomad4 FIN AF: 0.434

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.431

Alfa AF: 0.471 Hom.: 33647

Bravo AF: 0.413

Asia WGS AF: 0.530 AC: 1845 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
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

Oct 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	13
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0
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: rs2307130; hg19: chr1-100316589; COSMIC: COSV54056176; COSMIC: COSV54056176;