rs634880

chr1-99874669-G-Achr1-99874669-G-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.959-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,597,686 control chromosomes in the GnomAD database, including 407,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41324 hom., cov: 32)
  • Exomes 𝑓: 0.71 (365682 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.906

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 1-99874669-G-A is Benign according to our data. Variant chr1-99874669-G-A is described in ClinVar as [Benign]. Clinvar id is 256751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99874669-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.959-18G>A		intron_variant		ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.959-18G>A		intron_variant		1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111364 AN: 151696 Hom.: 41276 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.717 AC: 176020 AN: 245452 Hom.: 63332 AF XY: 0.717 AC XY: 95134 AN XY: 132622

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.711

Gnomad SAS exome AF: 0.733

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.725

GnomAD4 exome AF: 0.710 AC: 1026190 AN: 1445872 Hom.: 365682 Cov.: 32 AF XY: 0.709 AC XY: 510548 AN XY: 719644

Gnomad4 AFR exome AF: 0.848

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.704

Gnomad4 SAS exome AF: 0.731

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.734 AC: 111477 AN: 151814 Hom.: 41324 Cov.: 32 AF XY: 0.734 AC XY: 54466 AN XY: 74198

Gnomad4 AFR AF: 0.841

Gnomad4 AMR AF: 0.686

Gnomad4 ASJ AF: 0.652

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.678

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.730

Alfa AF: 0.711 Hom.: 39438

Bravo AF: 0.750

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	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 08, 2016

Variant summary: The AGL c.959-18G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 84126/115018 control chromosomes (30465 homozygotes) at a frequency of 0.731416, which is approximately 320 times the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	6.1
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs634880; hg19: chr1-100340225; COSMIC: COSV54049593;